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Leptomeningeal metastatic disease (LMD) from advanced malignancies has poor prognoses and limited treatments. Intrathecal therapy (ITT) protocols are available, showing variable outcomes. We reviewed the therapeutic and toxicity profiles of ITT in LMD.PubMed, EMBASE, Web-of-Science, and Scopus were searched following the PRISMA-ScR guidelines to include studies reporting ITT for LMD.gov and Cochrane were searched to identify ongoing clinical trials.We included 27 published studies encompassing 2161 patients and 4 ongoing trials. LMD originated from brain metastases (85.5%), lymphomas (5.4%), high-grade gliomas (4.6%), medulloblastomas (2.3%), and leukemias (2.1%). LMD was mostly diagnosed with the co-presence of neurological-related symptoms and positive imaging and/or cerebrospinal fluid cytology (60.8%). The most common ITT agents were methotrexate (35.9%), cytarabine (21.9%), and thiotepa (8.2%), standalone or combined. Patients received a median of 6.5 ITT cycles (range, 1.0-71.0) via intraventricular (58.8%) or lumbar intrathecal (41.2%) routes. The Ommaya reservoir was implanted in 38.5% cases. Concurrent systemic chemotherapy (45.2%) and/or radiotherapy (30.6%) were used. After 1-3 cycles, 44.7% patients had improved clinical status and 29.9% converted into negative cerebrospinal fluid cytology. The most common ITT-related severe adverse events were neutropenia (6.5%), meningitis (5.2%) and encephalopathy (4.5%). Median freedom from progression was 2.4 months (range, 0.1-59.5) and median overall survival 5.5 months (range, 0.1-148.0).Current ITT protocols are variable but effective and well-tolerated in LMD. Ongoing trials are investigating dose-limiting toxicity profiles and long-term overall survival. Future studies should analyze the therapeutic and safety profiles of ITT compared to newer systemic therapies.

Supplementary Figure from Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements

NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity–enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion–positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion–positive metastatic cancer were treated with Zeno. Two patients with ATP1B1–NRG1–positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74–NRG1-positive non–small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion–positive cancers.Significance:NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion–positive cancers and is thus an effective therapeutic strategy.This article is highlighted in the In This Issue feature, p. 1171

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686–95. ©2018 AACR.See related commentary by Wilson and Politi, p. 676.This article is highlighted in the In This Issue feature, p. 663

Table S1

Figures S1, S2, S3, S4, and S5

Supplementary Methods

NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity–enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion–positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion–positive metastatic cancer were treated with Zeno. Two patients with ATP1B1–NRG1–positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74–NRG1-positive non–small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion–positive cancers. Significance: NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion–positive cancers and is thus an effective therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1171

Purpose:MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear.Experimental Design:We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models.Results:Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models.Conclusions:KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.

Supplemental Figure 1

Supplementary Figure S2 shows that cell lines without NRG1 fusions are insensitive to seribantumab and the IC50 for inhibition of growth of cells by seribantumab.

Tumor volume changes and body weight changes in vivo in treated LUAD12C xenografts.

Supplementary Materials and Methods contains additional details of experimental procedures.

Supplementary Tables 1A and 1B

Purpose:The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.Patients and Methods:We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP).Results:MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.Conclusions:Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

Purpose:Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion–driven cancers.Experimental Design:We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo.Results:Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1 fusion) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%–100%. Afatinib was much less effective at blocking tumor growth.Conclusions:Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion–dependent tumorigenesis in vitro and in vivo in breast, lung, and ovarian patient-derived cancer models.

Supplementary Methods

Supplementary Methods

Purpose: Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion–driven cancers. Experimental Design: We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo. Results: Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1 fusion) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%–100%. Afatinib was much less effective at blocking tumor growth. Conclusions: Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion–dependent tumorigenesis in vitro and in vivo in breast, lung, and ovarian patient-derived cancer models.

Background: Vepafestinib (TAS0953/HM06, Vepa) is a 2nd generation RET-selective inhibitor that effectively penetrates the brain, and inhibits the wildtype RET kinase domain (KD) and RET KD mutants (G810, V804, Y806, L730) (presented at AACR-NCI-EROTC 2021 meeting). RET rearrangements are found in an increasing number of soft tissue sarcomas, including infantile fibrosarcoma (IFS). Here we investigated the efficacy of Vepa in comparison to other RET-selective inhibitors in preclinical models of pediatric sarcomas harboring RET fusions. Methods: Multiple preclinical models of SPECC1L::RET-driven sarcomas were established: 1) Paired patient-derived xenograft (PDX) and cell line models from a brain metastasis (BM) of an IFS tumor (SR-Sarc-0001); 2) A human mesenchymal stem cell line with RET fusion introduced with CRISPR-Cas9 (HMSC-RET); 3) A murine BM model produced by injection of luciferase-expressing HMSC-RET into the cerebellum. CNS penetration of Vepa was assessed by pharmacokinetic profiling in the prefrontal cortex (PFC), cerebrospinal fluid (CSF), and plasma in freely-moving male Han Wistar rats after oral administration of 3, 10, or 50 mg/kg single doses. Results: Exposure of SR-Sarc-0001 and HMSC-RET cells to Vepa resulted in dose- and time-dependent decreases in phosphorylation of RET, ERK1/2, AKT, STAT3 and S6, expression changes in cell cycle regulators (p27 up, cyclin D1 down), induction of pro-apoptosis proteins (c-PARP, BIM), and loss of MYC expression. Growth of SR-Sarc-0001 (IC50: 0.09 µM, 95% CI: 0.03-0.2) and HMSC-RET cells (IC50: 0.2 µM, 95% CI: 0.09-0.5), but not parental HMSC cells (IC50 > 1 µM), was suppressed by Vepa, with concomitant elevation of caspase 3/7 activity. Vepa was more effective than vandetanib and similar to the FDA-approved RET inhibitors, selpercatinib (Selp) and pralsetinib (Pral), in all in vitro assays. Significant regression of SR-Sarc-0001 PDX tumors was seen after Vepa treatment (64.8 ± 0.5%). Notably, no regrowth was observed up to 46 days after cessation of Vepa treatment, whereas 25 days after stopping Selp (10 mg/kg BID) and Pral (15 mg/kg BID) treatment, 1/5 and 3/5 tumors started to regrow, respectively. Similar efficacy was observed in the HMSC-RET xenograft model. Vepa was more effective than Selp at blocking HMSC-RET brain xenograft tumor growth (p=0.001) and increasing survival (p=0.0001). CNS penetration of Vepa was excellent, with near-equivalent concentrations detected in the PFC, CSF, and plasma-free fraction after equilibration between body fluid compartments. Conclusions: Our preclinical results suggest that vepafestinib has the potential to more effectively manage CNS metastasis compared to selpercatinib, representing a promising new therapeutic option for patients with RET-driven sarcomas. Vepafestinib is currently in a phase 1/2 trial for adult patients with advanced solid tumors harboring RET alterations (margaRET, NCT04683250). Citation Format: Igor Odintsov, Ryan C. Cheng, Allan J. Lui, Tom Zhang, Yue C. Lu, Renate I. Kurth, Morana Vojnic, Inna Khodos, Qing Chang, Kevin Chen, Claudio Giuliano, Annalisa Bonifacio, Isao Miyazaki, Elisa de Stanchina, Emanuela Lovati, Marc Ladanyi, Romel Somwar. Efficacy of vepafestinib in preclinical models of RET fusion-driven sarcoma models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4007.

Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

INTRODUCTION Brain metastases are the most common brain tumors and occur in 10-30% of cancer patients, whereas leptomeningeal disease (LMD) occurs in approximately 5% of adults with systemic malignancies. Tractable preclinical disease models that faithfully represent metastasis to the brain and recapitulate LMD are needed to improve our understanding of the biological basis of CNS disease as well developing effective therapeutic strategies. Our goal in this study was to generate representative preclinical disease models using two methods. METHODS We isolated tumor cells from CSF of 16 patients with cytologically proven LMD (9 NSCLC, 1 melanoma, 1 ovarian cancer, 1 endometrial cancer, and 4 breast cancer) and implanted the cells subcutaneously into the flank of immunocompromised mice. Cell lines were also generated from PDX tissues. Models were characterized by next-generation sequencing (NGS). We also generated a model of CNS metastasis of kinase-driven sarcoma by intracardiac (IC) injection of human mesenchymal stem cells (HMSC) expressing a SPECC1L::RET fusion (CRISPR-Cas9 gene editing). The cells (HMSC-RET) were also labeled with a luciferase construct to allow non-invasive bioluminescence imaging. RESULTS We established three PDX models (2 lung, 1 ovarian) from CSF (19% success rate compared to approximately 33% for solid tumors) and matched cell lines from the resulting PDX tissues. Intracardiac injection of HMSC-RET cells resulted in tumors establishing in several peripheral organs and the brain. SUMMARY AND CONCLUSIONS We have established disease models of CNS metastasis and LMD. Translational studies where patients with clinical suspicion of LMD undergo CSF sampling, NGS/ctDNA analysis, and PDX modeling are crucial in improving our understanding of this metastatic compartment and investigating novel treatment paradigms. Future studies will be focused on examining the biochemical and genetic nature of these tumors as well as developing effective therapeutic strategies.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper., Summary: Novel models of desmoplastic small round cell tumor (DSRCT) reveal a role for the ERBB pathway in regulating growth of this sarcoma and provide a rationale for evaluating EGFR antagonists in patients with DSRCT.

A 33-year-old man was admitted with a 4-week history of intermittent, right-sided chest pain. Two weeks before the incident, he had completed a 10-day course of levofloxacin for a presumed right-sided pneumonia without much improvement. He denied any dyspnea, cough, sputum production, hemoptysis, night sweats, or weight loss. He was an active smoker with a 20-pack-year smoking history and 1-year history of vaping nicotine.

2024 Background: Patients with RET fusion-positive NSCLC have an estimated 25% incidence of CNS metastasis at diagnosis, and up to 40% during disease progression. Effective anti-RET therapy that penetrates the blood-brain barrier is essential to extending survival. TAS0953/HM06 is a structurally distinct RET-specific inhibitor that exhibits a distinct binding mode to RET and is effective against RET solvent front (G810) and gatekeeper (V804) mutations. TAS0953/HM06 also inhibits growth of xenograft tumors established from RET fusion-driven tumors of multiple histologies. TAS0953/HM06, therefore, represents a potentially effective strategy to overcome the emergence of acquired resistance to first generation RET-selective inhibitors. Here, we compared the brain penetration and efficacy of TAS0953/HM06 to selpercatinib (FDA-approved RET inhibitor) in models of intracranial RET fusion-positive cancers, specifically NSCLC and sarcoma. Methods: We compared the brain: plasma ratio of unbound TAS0953/HM06 and selpercatinib in mice to determine the unbound partition coefficient, Kpuu, brain. We injected ECLC5 (NSCLC cell line, TRIM33-RET) and HMSC-RET (immortalized human mesenchymal stem cells in which SPECCL1-RET was introduced by CRISPR-Cas9 genomic engineering, sarcoma model) cells expressing luciferase into the cerebellum of mice. Tumor-bearing mice were treated with TAS0953/HM06 (50 mg/kg BID), selpercatinib (10 mg/kg BID) or vandetanib (multi-kinase RET inhibitor, 50 mg/kg QD), and assessed weekly for tumor growth via bioluminescence imaging. Results: Kpuu, brain, of TAS0953/HM06 and selpercatinib were 1.3 and 0.20, respectively. Substances with brain Kpuu > 0.3 in mice are regarded as brain-penetrable. TAS0953/HM06 was superior to selpercatinib at inhibiting growth of ECLC5 (p < 0.0001) and HMSC-RET (p = 0.0005) brain xenograft tumors, and increasing survival of tumor-bearing animals (ECLC5: TAS0953/HM06 139±0.5 days, selpercatinib 95+2.3 days, p = 0.002; HMSC-RET: TAS0953/HM06 41± 2.2 days, selpercatinib 20±3 days, p = 0.0001). Vandetanib, which is highly brain-penetrant, did not cause a significant decrease in growth of either brain tumor xenograft models. At the doses used, the 3 RET inhibitors induced similar regression in several peripheral subcutaneous xenograft tumor models. Conclusions: Our data in animal models suggest that TAS0953/HM06 penetrates the CNS more effectively than selpercatinib, and is superior at decreasing CNS disease and extending survival. TAS0953/HM06 represents a promising new therapeutic option for patients with RET fusions with acquired resistance mutations, including those with brain metastasis and those resistant to first-generation selective RET inhibitors. TAS0953/HM06 is currently undergoing a biomarker-driven phase 1/ 2 clinical trial for patients with solid tumors driven by RET alterations (NCT04683250).

Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1V573M and xDFG motif NTRK1G667C mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings., Romel Somwar et al. find that cancer-causing NTRK gene fusions resistant to one form of inhibitor therapy can be resistant to other inhibitor types. Using molecular simulations, they show that some NTRK1 mutations resistant to the type I inhibitor larotrectinib are hypersensitive to the type II inhibitor altiratinib, potentially due to the introduction of a sulfur moiety in the kinase binding pocket.

Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here, we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5′ fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and downregulated by treatment with cabozantinib, opening up potentially new therapeutic avenues for the combinatorial targetin of RET fusion- driven lung cancers. The novel RET fusion-dependent preclinical models described here represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies., Summary: Establishment of four patient-derived models of RET fusion-positive lung adenocarcinomas with three different RET fusions shows that MYC expression is regulated by RET.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) chromosomal translocation, which fuses the transcriptional regulatory domain of EWSR1 with the zinc finger DNA-binding domain of WT1, resulting in the oncogenic transcription factor EWS-WT1. DSRCT primarily affects young males and has a 5-year overall survival of about 15%. Typical treatment approaches for patients with DSRCT involve a multi-modal combination of surgery, chemotherapy and radiation. The paucity of DSRCT disease models has hampered functional and pre-clinical therapeutic studies in this aggressive cancer. Here, we developed robust preclinical disease models and mined DSRCT expression profiling data to identify genetic vulnerabilities that could be leveraged for the identification of rational therapies. Specifically, we developed four new DSRCT cell lines and one patient-derived xenograft (PDX) model. Transcriptomic and proteomic profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands and downstream signaling. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Conversely, targeting of EGFR using shRNA, small molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited growth and induced apoptosis in DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for the clinical evaluation of EGFR antagonists in patients with DSRCT.

BACKGROUND. Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is therefore a rational target for therapy in NRG1 fusion-driven cancers. METHODS. We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo. RESULTS. Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of pro-apoptotic proteins and reduced expression of the cell cycle regulator cyclin D1 were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3 and HBECp53-CD74-NRG1 cells with seribantumab, reduced phosphorylation of EGFR, HER2, HER3, HER4 and known downstream signaling molecules such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 PDX and OV-10–0050 (ovarian cancer with CUL-NRG1 fusion) PDX tumors induced regression of tumors by 50–100%. Afatinib was much less effective at blocking tumor growth. CONCLUSION. Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion-dependent tumorigenesis in vitro and in vivo in breast, lung and ovarian patient-derived cancer models.

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers. Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686–95. ©2018 AACR. See related commentary by Wilson and Politi, p. 676. This article is highlighted in the In This Issue feature, p. 663

We report a case of isolated immune thrombocytopenic purpura (ITP) as a result of babesiosis infection. The patient initially presented with a history, physical exam and laboratory findings consistent with idiopathic thrombocytopenic purpura. She was treated with standard of care therapy without clinical response. Daily evaluation of the peripheral smear ultimately revealed a red blood cell inclusion, identified and confirmed as a low-titer babesiosis infection indicative of past exposure. As described below, isolated thrombocytopenia related to babesiosis infection has not been reported prior to the patient's presentation. There are a few cases reported to show a relationship between babesiosis and autoimmune hemolytic anemia without an understood pathophysiologic mechanism. We review the literature, propose a possible pathophysiologic mechanism of disease and consider the implications of swift identification to prevent clinical deterioration. J Hematol. 2019;8(4):168-170 doi: https://doi.org/10.14740/jh570

Fusions involving RET receptor tyrosine kinase are a common driver of tumors across different tissue types, such as lung, thyroid, colorectal, soft tissue and others. TAS0953/HM06 (hereby referred to as HM06) is a novel 2ndgeneration RET-specific inhibitor that is effective against RET solvent front (G810) and gatekeeper (V804) mutations. Here, we evaluated the efficacy of HM06 in lung and thyroid carcinomas, and soft-tissue sarcoma cell lines and PDXs derived from RET inhibitor-naive tumor samples or from tumors with acquired resistance to selpercatinib. HM06 was more effective than the RET multi-kinase inhibitors cabozantinib and vandetanib, and as effective as selpercatinib and pralsetinib in inhibiting growth of patient-derived and isogenic lung, thyroid and sarcoma cell lines (IC50=0.02-0.1 µM) harboring different RET fusions (KIF5B-RET, CCDC6-RET, TRIM33-RET, SPECCL1-RET) or activating mutations (RET C634W). Growth of non-tumor cells was up to 80-fold less sensitive to HM06 (IC50= 1.6 µM). Treatment of RET fusion-positive lung cancer cells with HM06 resulted in a dose-dependent inhibition of RET phosphorylation (Y905 and Y1062) and the downstream effectors AKT, ERK1/2, p70S6K and S6. Caspase 3/7 activity and markers of apoptosis (BIM, cleaved PARP) were induced by HM06 to a similar extent as pralsetinib and selpercatinib (dose range: 0.05-1 µM). HM06 induced changes in the core mediators of cell cycle regulation (upregulation of p27, downregulation of CCND1) and suppressed expression of MYC and ETV5. In vivo, HM06 blocked tumor growth and/or induced regression of up to 65% in seven patient-derived xenograft (PDX) models with RET fusions (five NSCLC PDXs, one sarcoma PDX and one NSCLC cell-line xenograft) to a similar extent as pralsetinib and selpercatinib. However, 6 weeks after cessation of treatment of the SPECCL1-RET-driven sarcoma PDX model, growth of tumors treated with HM06 was suppressed completely, whereas 3/5 pralsetinib-treated tumors and 1/5 selpercatinib-treated tumor regrew. Combination of HM06 and the MET inhibitor capmatinib effectively blocked growth of PDX tumors in a model that was derived from a patient sample that expressed RET fusion and METamplification, and was resistant to selpercatinib. These results suggest that HM06 may be an effective therapy for RET-driven tumors in a tissue-type agnostic manner and can effectively address common on-target and off-target resistance mechanisms such as RET G810X and V804X mutations. HM06 is currently in a phase 1 and 2 clinical trial for patients with advanced solid tumors with RET gene abnormalities (margaRET, NCT 04683250). Citation Format: Igor Odintsov, Renate I. Kurth, Kota Ishizawa, Lukas Delasos, Allan J.W. Lui, Inna Khodos, Connor J. Hagen, Qing Chang, Marissa S. Mattar, Morana Vojnic, Siddharth Kunte, Annalisa Bonifacio, Claudio Giuliano, Elisa De Stanchina, Emily Cheng, Emanuela Lovati, Marc Ladanyi, Romel Somwar. TAS0953/HM06 is effective in preclinical models of diverse tumor types driven by RET alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P233.

Background. Oncogenic rearrangements of the neuregulin 1 gene (NRG1) consist of a 5' partner fused to a 3' NRG1 sequence that retains the EGF-like domain, and are found in 0.2% of solid tumors including lung, breast and gastrointestinal (GI) cancers. Carcinomas of GI origin, including pancreatic and cholangiocarcinoma, represent around 20% of solid tumors harboring NRG1 fusions and there is no approved therapy for this group of cancers. The chimeric NRG1 oncoproteins bind to HER3/ERBB3 leading to trans-activation of other ERBB family members and trigger a signaling cascade that culminates in oncogenesis. Although targeting HER3 represents a rational therapeutic strategy for cancers harboring NRG1 fusions, this has remained relatively unexplored for NRG1 fusion-positive GI malignancies. In this study we investigated the efficacy of the anti-HER3 monoclonal antibody seribantumab in preclinical models of NRG1-driven GI cancers. Methods. We developed models of isogenic pancreatic cancer cells with NRG1 fusions by lentiviral-mediated cDNA expression of ATP1B1-NRG1 and SLC3A2-NRG1 fusions in immortalized pancreatic ductal cells (H6c7). Seribantumab efficacy was evaluated in isogenic cell lines and in patient-derived xenograft (PDX) models of pancreatic adenocarcinoma (CTG-0943, APP-NRG1 fusion) and intrahepatic cholangiocarcinoma (CH-07-0068, RBPMS-NRG1 fusion). Western blotting analysis was used to evaluate protein phosphorylation. Expression of NRG1 fusions was confirmed by RT-PCR and NGS. Results. Expression of NRG1 fusions in H6c7 cells resulted in enhanced phosphorylation of HER3 and AKT and increased sensitivity to afatinib, as compared to empty vector control cells (H6c7-EV). Treatment of H6c7-SLC3A2-NRG1 cells with seribantumab resulted in a dose-dependent inhibition of HER3 and AKT phosphorylation. Seribantumab treatment of H6c7-ATP1B1-NRG1 and H6c7-SLC3A2-NRG1 cells resulted in dose-dependent inhibition of cell growth with IC50 values of 0.05 and 0.2 µM, respectively. In contrast, growth of H6c7-EV cells was much less sensitive to seribantumab (IC50 > 1µM). Tumor growth inhibition was observed after administration of seribantumab to PDX mouse models of pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma. While seribantumab (5 mg and 10 mg per dose, BIW) was equally effective to the clinical equivalent dose of afatinib (5 mg/kg QD) in the cholangiocarcinoma PDX model, the two doses of seribantumab were more effective than afatinib in the pancreatic cancer PDX model, causing tumor shrinkage of up to 55% (23-77% range). There was no shrinkage of afatinib-treated pancreatic PDX tumors. Our results here suggest that seribantumab is effective at reducing tumor growth in preclinical models of gastrointestinal cancers with NRG1 fusions. These data support the use of seribantumab to treat GI and other cancers with NRG1 fusions in the ongoing phase 2 CRESTONE study (NCT#04383210). Citation Format: Igor Odintsov, Allan J. Lui, Paul R. Bloom, Morana Vojnic, Shawn Leland, Marc Ladanyi, Romel Somwar. Preclinical activity of seribantumab in gastrointestinal cancers with NRG1 fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 935.

Introduction Multiple genetic mechanisms have been identified in EGFR-mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs), but many cases still lack a known mechanism. Methods To identify novel mechanisms of AR, we performed targeted large panel sequencing of samples from 374 consecutive patients with metastatic EGFR-mutant lung cancer, including 174 post-TKI samples, of which 38 also had a matched pre-TKI sample. Alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, and PC9) by using clustered regularly interspaced short palindromic repeats/Cas9 genome editing. MSK-LX138cl, a cell line with EGFR exon 19 deletion (ex19del) and praja ring finger ubiquitin ligase 2 gene (PJA2)/BRAF fusion, was generated from an EGFR TKI–resistant patient sample. Results We identified four patients (2.3%) with a BRAF fusion (three with acylglycerol kinase gene (AGK)/BRAF and one with PJA2/BRAF) in samples obtained at AR to EGFR TKI therapy (two posterlotinib samples and two posterlotinib and postosimertinib samples). Pre-TKI samples were available for two of four patients and both were negative for BRAF fusion. Induction of AGK/BRAF fusion in H1975 (L858R + T790M), PC9 (ex19del) and HCC827 (ex19del) cells increased phosphorylation of BRAF, MEK1/2, ERK1/2, and signal transducer and activator of transcription 3 and conferred resistance to growth inhibition by osimertinib. MEK inhibition with trametinib synergized with osimertinib to block growth. Alternately, a pan-RAF inhibitor as a single agent blocked growth of all cell lines with mutant EGFR and BRAF fusion. Conclusion BRAF fusion is a mechanism of AR to EGFR TKI therapy in approximately 2% of patients. Combined inhibition of EGFR and MEK (with osimertinib and trametinib) or BRAF (with a pan-RAF inhibitor) are potential therapeutic strategies that should be explored.

PURPOSE: MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear. EXPERIMENTAL DESIGN: We examined clinical and genomic data from 113 lung cancer patients with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models. RESULTS: Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS co-occurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. CONCLUSIONS: KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort. (245/250 words) TRANSLATIONAL RELEVANCE: METex14 alterations have emerged as one of the most common targetable alterations in non-small cell lung cancers, and are amenable to MET kinase inhibitor therapy; however, inhibitor activity can be limited by primary or acquired genomic aberrations that lead to therapeutic resistance, warranting the investigation of alternative therapeutic approaches. We show that concurrent KRAS mutation is more common in the setting of METex14 than with other major drivers (e.g. sensitizing EGFR and ALK alterations), and confers primary or secondary resistance to MET-directed therapies in METex14-altered lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. These results provide a rationale for clinical evaluation of these combination approaches. (115/120–150 words)

BACKGROUND: CNS metastases occur in 20–50% of lung cancer patients during their disease; leptomeningeal disease (LMD) representing 5–8%, classically carries a poor prognosis with a median overall survival ranging from 1–11 months. There is a paucity of patient-derived preclinical disease models using tumor cells isolated from the CSF. Models that faithfully recapitulate the biology of CNS tumors would offer new insights into the biology of the disease as well as provide the basis for developing more effective therapy. METHODS: To create more representative preclinical models to study LMD we isolated tumor cells from CSF of 5 patients with cytologically proven LMD and implanted the cells into the subcutaneous flank of immune-compromised mice. Where possible, cell lines were also generated from PDX tissues. Models were characterized by next generation sequencing (NGS), growth rates, expression of driver oncogenes and sensitivity to small molecule inhibitors. RESULTS: To date, one PDX (LUAD-0048A) and cell line model were successfully derived from CSF samples (NSCLC patient with MET amplification) and 4 are pending. MET amplification and mRNA over-expression were confirmed by quantitative PCR in the PDX tissue and the cell line. Western blot analysis indicated that over-expressed MET was phosphorylated in both PDX tissue and cell line. These results were confirmed by immunohistochemistry. Growth of LUAD-0048A cells were unaffected by 3 MET inhibitors (crizotinib, cabozantinib, glesatinib). Similarly, MET inhibitors did not induce apoptosis in the cells. CONCLUSION: LMD represents an aggressive metastatic event in lung cancer patients. Here we were able to successfully establish a PDX from the CSF of a patient with LMD and trial targeted therapies in vivo. Translational collaborations where patients with clinical suspicion of LMD undergo CSF sampling, NGS/ctDNA analysis, and PDX modeling are crucial in improving our understanding of this metastatic compartment and investigating novel treatment paradigms.

Mutations in MET that induce skipping of exon 14 and lead to reduced ubiquitin ligase-mediated turnover of this receptor tyrosine kinase (RTK) are detected in 3-4% of non-small cell lung cancer (NSCLC), approaching the prevalence of ALK-rearranged lung cancers. Preclinical and clinical studies have revealed that MET exon14 alterations are actionable oncogenic drivers that are amenable to therapy with MET kinase inhibitors such as crizotinib. However, similar to most kinase-driven cancers, despite initial benefit, acquired resistance to therapy is inevitable. Next-generation sequencing (MSK-IMPACT 468 gene panel) was performed on samples from 81 NSCLC patients with MET exon14 alterations, including 7 with paired pre- and post-treatment tumor samples. A concurrent KRAS G12 mutation was identified in 5 patients. In 4 of these patients, the KRAS mutation was present prior to receiving crizotinib. The KRAS mutation was acquired post-crizotinib in the remaining patient. These findings implicate KRAS activation as a potential mechanism of acquired resistance. Using isogenic and patient-derived in vitro and in vivo models harboring MET exon14 skipping alteration, we confirmed that the KRAS mutation results in constitutive activation of RAS/ERK signaling and cells expressing both MET exon14 skipping and KRAS mutations are refractory to MET inhibition. Dual inhibition of MET and MEK with crizotinib and trametinib, respectively, has an additive effect in cell line and xenograft models. Whereas concurrent KRAS mutation is an extremely rare event in EGFR- and ALK-driven NSCLC, our findings confirm KRAS mutation as a recurrent mechanism of primary or secondary resistance to MET-directed therapies in lung cancers harboring MET exon14 alterations. We provide a new potential therapeutic strategy for NSCLC patients with both MET exon14 alterations and KRAS mutations. Citation Format: Ken Suzawa, Michael D. Offin, Christopher Kurzatkowski, Daniel Liu, Morana Vojnic, Roger S. Smith, Marissa Mattar, Inna Khodos, Elisa de Stanchina, Joshua K. Sabari, William W. Lockwood, Alexander E. Drilon, Marc Ladanyi, Romel Somwar. Oncogenic KRAS mediates resistance to MET targeted therapy in non-small cell lung cancer (NSCLC) with MET mutations that induce exon14 skipping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1826.

12122Background: While multiple genetic mechanisms have been identified in EGFR mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKI), either first g...