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Supplementary Table legends 1-2

Therapeutic cancer vaccines targeting melanoma-associated antigens are commonly immunogenic but are rarely effective in promoting objective clinical responses. To identify critical molecules for activation of effective antitumor immunity, we have profiled autologous dendritic cell (DC) vaccines used to treat 35 patients with melanoma. We showed that checkpoint molecules induced by ex vivo maturation correlated with in vivo DC vaccine activity. Melanoma patient DCs had reduced expression of cell surface inducible T-cell costimulator ligand (ICOSL) and had defective intrinsic NF-κB signaling. Chromatin immunoprecipitation assays revealed NF-κB–dependent transcriptional regulation of ICOSL expression by DCs. Blockade of ICOSL on DCs reduced priming of antigen-specific CD8+ and CD4+ T cells from naïve donors in vitro. Concentration of extracellular/soluble ICOSL released from vaccine DCs positively correlated with patient clinical outcomes, which we showed to be partially regulated by ADAM10/17 sheddase activity. These data point to the critical role of canonical NF-κB signaling, the regulation of matrix metalloproteinases, and DC-derived ICOSL in the specific priming of cognate T-cell responses in the cancer setting. This study supports the implementation of targeted strategies to augment these pathways for improved immunotherapeutic outcomes in patients with cancer.

Supplementary Tables 1-2

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Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC (NCT03214250). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

Therapeutic cancer vaccines targeting melanoma-associated antigens are commonly immunogenic but are rarely effective in promoting objective clinical responses. To identify critical molecules for activation of effective antitumor immunity, we have profiled autologous dendritic cell (DC) vaccines used to treat 35 patients with melanoma. We showed that checkpoint molecules induced by ex vivo maturation correlated with in vivo DC vaccine activity. Melanoma patient DCs had reduced expression of cell surface inducible T-cell costimulator ligand (ICOSL) and had defective intrinsic NF-κB signaling. Chromatin immunoprecipitation assays revealed NF-κB–dependent transcriptional regulation of ICOSL expression by DCs. Blockade of ICOSL on DCs reduced priming of antigen-specific CD8+ and CD4+ T cells from naïve donors in vitro. Concentration of extracellular/soluble ICOSL released from vaccine DCs positively correlated with patient clinical outcomes, which we showed to be partially regulated by ADAM10/17 sheddase activity. These data point to the critical role of canonical NF-κB signaling, the regulation of matrix metalloproteinases, and DC-derived ICOSL in the specific priming of cognate T-cell responses in the cancer setting. This study supports the implementation of targeted strategies to augment these pathways for improved immunotherapeutic outcomes in patients with cancer.

BackgroundA first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2+ patients with advanced melanoma.MethodsPatient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-γ enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins.ResultsSixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against ≥3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8+ T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis.ConclusionsCombined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents.Trial registration numberNCT01876212.

2548 Background: Circulating tumor DNA (ctDNA) is increasingly used as a prognostic marker with high ctDNA shedding associated with poor survival. Gene-, but not variant-specific, differences in ctDNA shedding have been reported. Tumor burden, mitotic rate, and cell death rate have been proposed as contributors to ctDNA shedding. Here we investigate associations of ctDNA shedding for the two most common mPDAC KRAS variants, G12D and G12V, with tumor burden, mitotic score, and overall survival (OS). Methods: Pretreatment (baseline) ctDNA was analyzed by droplet digital PCR for 86 (including 44 G12D, 30 G12V) patients with mPDAC receiving front-line chemoimmunotherapy in a randomized open-label Phase II study (NCT03214250). Baseline tumor burden in total, within the pancreas, and distally, was assessed by sum of RECIST target lesion diameters. Tumor tissue variant allele fraction (tVAF) and mitotic score (geometric mean expression of 65 mitosis-associated genes) were calculated from DNA and RNA sequencing. Results: ctKRAS shedding (dichotomized at median mutant copies/mL) was associated with OS for G12D bearing tumors (p = 0.03) but not G12V (p = 0.17, log-rank test). To identify variant-specific features of shedding, we examined the Spearman correlation for total tumor burden and ctKRAS shedding; G12D but not G12V shedding was correlated with tumor burden (p = 0.01 and p = 0.22 respectively). However, the higher tVAF in G12V compared to G12D tumors (p = 0.048, Mann-Whitney test) could result from differences in purity, ploidy, and KRAS copy number. Thus, we used tVAF as a scalar to calculate an adjusted tumor burden which was significantly correlated with both G12D and G12V ctDNA shedding (p = 0.004 and 0.02, respectively). When a patient’s distal vs. pancreatic lesions were analyzed separately, pancreatic tumor burden was not correlated with G12D or G12V shedding (p = 0.10 and 0.33, respectively) but distal burden was correlated with both (p = 0.001 and 0.02, respectively). While there was no difference by KRAS variant for the correlation between adjusted tumor burden and shedding, these results do suggest that, in patients with mPDAC, distal rather than primary tumor burden may drive ctDNA shedding. Finally, tumor mitotic rate was combined with adjusted total tumor burden in a linear regression model; both were significant for predicting G12D shedding (p = 0.007 and p < 0.0001, respectively) but not for G12V (p = 0.045 and p = 0.16, respectively). Conclusions: These data suggest that ctDNA shedding and survival associations may be KRAS variant-specific in mPDAC. Tumor mitotic score and location of tumors may explain some variant-specific differences in shedding. As clinical ctDNA tests become more widely used, further investigation of variant-specific shedding in KRAS and other genes may be key for proper interpretation of ctDNA tests.

4010 Background: Preclinical and small clinical studies of chemoimmunotherapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) point to a yet unrealized potential of clinically significant immune activation. In our phase II study of the CD40 agonist antibody sotigalimab (sotiga) and/or nivolumab (nivo) with gemcitabine and nab-paclitaxel (chemo), we observed promising improvements in overall survival (OS) in 105 patients with newly diagnosed mPDAC (NCT03214250); the primary endpoint of 1-year OS rate was 57.7% (p = 0.006) in the nivo/chemo arm, 48.1% (p = 0.062) in the sotiga/chemo arm and 41.3% (p = 0.233) in the nivo/sotiga/chemo arm (O’Hara, ASCO 2021) as compared to a historical control of 35%. Here, we report results of multi-omic translational analyses designed to identify signatures predictive of OS benefit. Methods: Longitudinal blood and tumor tissue samples were collected for immune and tumor biomarker analysis. Tumor samples underwent RNA sequencing and multiplex immunofluorescence (mIF). Peripheral blood was analyzed by mass cytometry time of flight (CyTOF), high parameter flow cytometry, and proteomics. Machine learning (ML) algorithms were applied to the data to identify biosignatures related to OS in each arm. Results: Comprehensive multi-omic, multi-parameter immune and tumor biomarker analyses identified distinct pretreatment immune signatures predictive of longer OS specific to nivo/chemo or sotiga/chemo (Table, representative examples). Because patients in each arm received chemotherapy, these and other arm-unique biomarkers suggest a relationship to the immunotherapy rather than chemotherapy in this randomized study. There was evidence of immune exhaustion in the sotiga/nivo/chemo arm that may explain the lack of survival benefit. Conclusions: From in-depth translational and ML analyses of randomized phase II trial of first-line chemoimmunotherapy in mPDAC patients, we identified novel biomarkers that associated with OS distinctly in each arm. Clinical trials in first-line mPDAC exploiting these previously unappreciated biomarkers and aiming to enrich patients for response, are warranted to further advance chemoimmunotherapy in this disease. Clinical trial information: NCT03214250. [Table: see text]

Background The therapeutic efficacy of Dendritic cells (DC) vaccines remains low and there is an unmet need for more effective vaccine design to achieve durable clinical outcomes. Our study analyzed the transcriptomic and energetic metabolism profile of an adenoviral-based DC vaccine targeted against three commonly shared melanoma antigens: Tyrosinase, MART-1 and MAGE-A6 from 35 subjects enrolled in a Phase I study of autologous DC vaccines in late-stage melanoma.1 To further investigate the immuno-metabolic features of monocyte-derived DC vaccines, we are employing a novel flow cytometry-based method, called SCENITH2 to integrate functional metabolic states with multiparametric DC immune phenotypes. Methods iDC were generated from HD and patient monocytes using GM-CSF+IL-4 for 5d. DC were matured (mDC) using IFN?+LPS for additional 24 hrs. Tolerogenic DC (Tol DC) were generated using vitamin-D3 and dexamethasone. Seahorse® was used to measure DC metabolic profile. Cytek/Aurora spectral flow cytometry was used for multiparametric-phenotypic and metabolic analysis by SCENITH™. Results Melanoma patient mDC used for autologous vaccine generation showed significantly altered metabolic gene signatures associated with enhanced oxidative phosphorylation (OXPHOS) and lipid metabolism pathways as compared to HD mDC. Furthermore, increased enrichment for mitochondrial respiration genes involved in the TCA cycle, electron transport chain and fatty acid oxidation (FAO) correlated with inferior tumor antigen-specific T cell responses and clinical outcome in patients. Seahorse analyses confirmed that HD and good outcome patient DC demonstrated the highest maturation-induced reduction in maximal oxygen consumption rate/OXPHOS and exogenous FAO. Interestingly, while the glycolytic rate of non-responding patient DC was the lowest, overall, we observe only a moderate increase in glycolytic capacity during DC maturation. SCENITH analysis showed that unlike monocytes, which are primarily glycolytic, differentiated mono-derived iDC and mDC utilize both glycolysis and mitochondrial respiration. Interestingly, under tolerogenic (Tol) differentiation conditions Tol iDC shift from glucose dependence into FAO and/or glutaminolysis while Tol mDC strongly depend on OXPHOS. Consistent with dependence on mitochondrial respiration, Tol mDC exhibit reduced HIF1a levels together with enhanced p-AMPK:p-mTOR ratio. Additionally, we show that the altered metabolism of Tol mDC is linked to retention of CD14-monocyte antigen with reduced DC markers HLA-DR, CD86, CD206, CD11c, CD33, with increased PD-L1 and ILT3 expression. Furthermore, we show that unlike HD mDC, tolerogenic and melanoma patient-derived mDC populations exhibit similar metabolic and immune characteristics. Conclusions We demonstrate that metabolic profile of DCs is tightly associated to the immuno-stimulatory potential of DC vaccines from cancer patients. Using SCENITH, we linked phenotypic and functional metabolic changes associated to immune signatures that correspond to heathy and immuno-suppressed DC differentiation. Ethics Approval The clinical trial reported was fully approved by the Univ. Pittsburgh PRC and IRB (PRO12010416, #09–021) and had FDA IND #15044 and NCT01622933. References Butterfield LH, Vujanovic L, Santos PM, Maurer DM, Gambotto A, Lohr J, Li C, Waldman J, Chandran U, Lin Y, et al. Multiple antigen-engineered DC vaccines with or without IFNalpha to promote antitumor immunity in melanoma. Journal for immunotherapy of cancer 2019;7:113. Arguello RJ, Combes AJ, Char R, Bousiquot E, Gigan JP, Camosseto V, Samad B, Tsui J, Yan P, et al. SCENITH: A flow cytometry based method for functional profiling energy metabolism with single cell resolution. BioRxiv 2020.03.10.985796; doi: https://doi.org/10.1101/2020.03.10.985796. Cell Metabolism. (Sneak and Peek: under review 10.2139/ssrn.3565001)

BackgroundGemcitabine/nab-Paclitaxel (GnP) is a standard of care regimen for first-line metastatic pancreatic ductal adenocarcinoma (PDAC) and has a 1-year overall survival (OS) rate of approximately 35%. There is an urgent need for novel therapeutics and precision medicine approaches in PDAC. PRINCE, a randomized phase 2 trial, reported an increased 1-year OS relative to historical data, for patients treated with nivolumab (nivo)/GnP (57.3%, p = 0.007, n=34) and sotigalimab (sotiga) (APX005M; CD40 agonist)/GnP (48.1%, p = 0.062, n= 36).MethodsTo investigate immune modulatory and pharmacodynamic (PD) effects of nivo or sotiga in combination with GnP we used several orthogonal minimally invasive, blood-based biomarker technologies. Immune population profiles were evaluated by CyTOF and features of T cell phenotype and function by multicolor flow cytometry. Soluble proteins were evaluated with predefined panels using the Olink platform (Immuno-oncology (IO) and Immune Response) along with an unbiased mass spectrometry proteomic approach (Biognosys) that identified circulating soluble proteins of significance.ResultsRelative to baseline, patients who received nivo/GnP had numerically increased frequencies of proliferating, activated CD8+ and CD4+ effector memory T cells in circulation across multiple timepoints. These patients also had significantly increased levels of soluble proteins associated with type II interferon responses and immune cell migration and T cell activation, as well as significantly decreased levels of immunomodulatory proteins.Patients who received sotiga/GnP had increased expression of the co-stimulatory molecule CD86 on conventional dendritic cells. These patients also had significantly increased concentrations of soluble proteins associated with mature antigen presenting cells, and the activation of helper CD4+ T cells, B cells, and monocytes. Significant increases in soluble proteins associated with type-1 cell-mediated effector immunity and decreases in immunosuppressive factors were observed in both arms. Significant proteins were defined as p ≤ 0.05, log2 expression fold change ≥ 0.5 (Olink) and Sparse PLS discriminant analysis was used with zero as a threshold (Biognosys).ConclusionsThis study is a first to use multiomic minimally invasive biomarker approaches in PDAC to demonstrate PD effects and immune modulation with immunotherapy/chemotherapy combinations. Orthogonal assays demonstrate that nivo/GnP and sotiga/GnP elicit unique immune responses and the observed effects are consistent with their distinct mechanisms of action. These data suggest that multiomic biomarker signatures may identify subsets of patients who may benefit from an immunotherapy/chemo approach in PDAC. Moreover, results from these analyses will support early phase clinical study development decisions.AcknowledgementsWe extend our gratitude to the patients, their families, the clinical investigators, and their site staff members who are making this trial possible. We would also like to thank Sultan Nawabi at Parker Institute for Cancer Immunotherapy (PICI) for operations leadership of the trial. We thank Bristol Myers Squibb (BMS) and Apexigen for collaboration and study drugs. The study was funded by Cancer Research Institute, BMS and PICI.Trial RegistrationNCT03214250Ethics ApprovalThis study was approved by University of Pennsylvania Institutional Review Board; Federalwide assurance #00004028.

Background Various proinflammatory cytokines can be detected within the melanoma tumor microenvironment. Interleukin 32 (IL32) is produced by T cells, NK cells and monocytes/macrophages, but also by a subset of melanoma cells. We sought to better understand the biology of IL32 in human melanoma. Methods We analyzed RNA sequencing data from 53 in-house established human melanoma cell lines and 479 melanoma tumors from The Cancer Genome Atlas dataset. We evaluated global gene expression patterns associated with IL32 expression. We also evaluated the impact of proinflammatory molecules TNFα and IFNγ on IL32 expression and dedifferentiation in melanoma cell lines in vitro. In order to study the transcriptional regulation of IL32 in these cell lines, we cloned up to 10.5 kb of the 5′ upstream region of the human IL32 gene into a luciferase reporter vector. Results A significant proportion of established human melanoma cell lines express IL32, with its expression being highly correlated with a dedifferentiation genetic signature (high AXL/low MITF). Non IL32-expressing differentiated melanoma cell lines exposed to TNFα or IFNγ can be induced to express the three predominant isoforms (α, β, γ) of IL32. Cis-acting elements within this 5′ upstream region of the human IL32 gene appear to govern both induced and constitutive gene expression. In the tumor microenvironment, IL32 expression is highly correlated with genes related to T cell infiltration, and also positively correlates with high AXL/low MITF dedifferentiated gene signature. Conclusions Expression of IL32 in human melanoma can be induced by TNFα or IFNγ and correlates with a treatment-resistant dedifferentiated genetic signature. Constitutive and induced expression are regulated, in part, by cis-acting sequences within the 5′ upstream region. Electronic supplementary material The online version of this article (10.1186/s12967-019-1862-y) contains supplementary material, which is available to authorized users.

It has been known for decades that the immune system can be spontaneously activated against melanoma. The presence of tumor infiltrating lymphocytes in tumor deposits is a positive prognostic factor. Cancer vaccination includes approaches to generate, amplify, or skew antitumor immunity. To accomplish this goal, tested approaches involve administration of tumor antigens, antigen presenting cells or other immune modulators, or direct modulation of the tumor. Because the success of checkpoint blockade can depend in part on an existing antitumor response, cancer vaccination may play an important role in future combination therapies. In this review, we discuss a variety of melanoma vaccine approaches and methods to determine the biological impact of vaccination.

Background Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Cancer vaccination may be more efficacious in combination with additional interventions that may build on or amplify their effects. Methods Based on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8+ and CD4+ T cell response against three shared melanoma antigens. The 35 vaccine recipients were then randomized to receive one month of high-dose IFNα or observation. Results The resulting clinical outcomes were 2 partial responses, 8 stable disease and 14 progressive disease among patients with measurable disease using RECIST 1.1, and, of 11 surgically treated patients with no evidence of disease (NED), 4 remain NED at a median follow-up of 3 years. The majority of vaccinated patients showed an increase in vaccine antigen-specific CD8+ and CD4+ T cell responses. The addition of IFNα did not appear to improve immune or clinical responses in this trial. Examination of the DC vaccine profiles showed that IL-12p70 secretion did not correlate with immune or clinical responses. In depth immune biomarker studies support the importance of circulating Treg and MDSC for development of antigen-specific T cell responses, and of circulating CD8+ and CD4+ T cell subsets in clinical responses. Conclusions DC vaccines are a safe and reliable platform for promoting antitumor immunity. This combination with one month of high dose IFNα did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC. Trial registration NCT01622933. Electronic supplementary material The online version of this article (10.1186/s40425-019-0552-x) contains supplementary material, which is available to authorized users.

The c-Met (MET) receptor and its ligand, hepatocyte growth factor (HGF), have been shown to mediate epithelial-mesenchymal transition (EMT), proliferation, invasion, motility, and angiogenesis. The HGF/MET pathway is frequently altered in non-small cell lung cancer (NSCLC) and has emerged as a targetable oncogenic driver, as patients with MET amplification and/or mutations have demonstrated marked responses to the MET tyrosine kinase inhibitor (TKI), crizotinib. However, long-term efficacy of MET TKIs is limited as acquired resistance is inevitable and almost half of patients with MET alterations fail to respond to MET TKIs. HGF overexpression has been identified as a mechanism of resistance to both MET and EGFR TKIs in MET altered and EGFR mutant NSCLC. Furthermore, MET amplification has been implicated in EGFR TKI resistance. However, the mechanism(s) by which the HGF-MET pathway causes resistance are poorly understood. We have previously shown that the EMT-transcription factor, TWIST1, is required for MET-driven NSCLC. Here, we investigated the requirement of TWIST1 in HGF-mediated resistance to MET and EGFR TKIs and the role of TWIST1 in de novo and acquired resistance to MET and EGFR TKIs. We found that HGF treatment induced EMT in NSCLC cell lines and increased TWIST1 protein expression through a post-translational mechanism. We demonstrated that targeting TWIST1 pharmacologically with the TWIST1 inhibitor, harmine, overcame HGF-mediated resistance to both MET and EGFR TKIs in MET and EGFR-driven NSCLC. This suggests that TWIST1 is specifically required for HGF-mediated resistance to targeted therapies. We also found that TWIST1 is overexpressed in a subset of MET and EGFR altered cell lines and TWIST1 overexpression was sufficient to cause resistance to MET and EGFR TKIs. In MET-driven and EGFR mutant cell lines that express TWIST1 and are resistant to targeted therapies, we demonstrated that harmine treatment resensitized resistant cells to MET and EGFR TKIs, respectively. To investigate the role of TWIST1 overexpression in Hgf-driven lung cancer, we utilized a CCSP-Hgf (CH) mouse model that constitutively overexpresses Hgf in the lung and develops crizotinib-sensitive tumors following treatment with the tobacco carcinogen, nicotine-derived nitrosamine ketone (NNK). We demonstrated that the Twist1 overexpressing CTH (CCSP-rtTA/Twist1-tetO-luc/CCSP-Hgf) mice developed significantly larger tumors in response to NNK as compared to CH and CCSP-rtTA/Twist1-tetO-luc (CT) mice. In summary, we established that HGF-regulated TWIST1 expression and that TWIST1 expression is required for resistance to MET and EGFR TKIs in the presence and absence of HGF overexpression. These studies suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome HGF-MET-driven resistance in EGFR mutant NSCLC as well as MET TKI resistance in MET-driven NSCLC. Citation Format: Zachary A. Yochum, Suman Chatterjee, Eric H. Huang, Deena M. Maurer, Myriam A. Attar, Sanja Dacic, Laura P. Stabile, Timothy F. Burns. TWIST1 is a key mediator of HGF-MET-driven resistance to targeted therapies in EGFR mutant and MET-driven lung cancer [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 5889.