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Human epidermal growth factor receptor 2 (HER2) aberrations are observed in various cancers. In non-small cell lung cancer, genetic alterations activating HER2, mostly exon 20 insertion mutations, occur in approximately 2-4% of cases. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate has been approved as the first HER2-targeted drug for HER2-mutant lung cancer. However, some cases are not responsive to T-DXd and the primary resistant mechanism remains unclear. In this study, we assessed sensitivity to T-DXd in JFCR-007, a patient-derived HER2-mutant lung cancer cell line. Although JFCR-007 was sensitive to HER2 tyrosine kinase inhibitors, it showed resistance to T-DXd in attachment or spheroid conditions. Accordingly, we established a three-dimensional (3D) layered co-culture model of JFCR-007, where it exhibited a lumen-like structure and became sensitive to T-DXd. In addition, an in-house inhibitor library screening revealed that G007-LK, a tankyrase inhibitor, was effective when combined with T-DXd. G007-LK increased the cytotoxicity of topoisomerase-I inhibitor, DXd, a payload of T-DXd and SN-38. This combined effect was also observed in H2170, an HER2-amplified lung cancer cell line. These results suggest that the proposed 3D co-culture system may help in evaluating the efficacy of T-DXd and may recapitulate the tumor microenvironment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ryohei Katayama reports financial support was provided by Japan Society for the Promotion of Science. Ryohei Katayama reports financial support was provided by Japan Agency for Medical Research and Development. Ryohei Katayama reports financial support was provided by the Nakatomi Foundation. Ryohei Katayama reports financial support was provided by Nippon Foundation. Ryohei Katayama reports financial support was provided by Takeda Science Foundation. Ryohei Katayama reports financial support was provided by Kobayashi Foundation for Cancer Research. Ken Uchibori reports financial support was provided by Japan Society for the Promotion of Science. Akari Shiraishi reports financial support was provided by Japan Science and Technology Agency. Ryohei Katayama reports a relationship with Chugai Pharmaceutical Co Ltd that includes: funding grants. Ryohei Katayama reports a relationship with Toppan Inc that includes: funding grants. Yuki Takahashi reports a relationship with Toppan Inc that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Vascular endothelial growth factor-A (VEGF-A) plays important roles in tumor immune suppression and thus correlates with the efficacy of anti-programmed cell death-1/ligand 1 (anti-PD-1/PD-L1) antibodies. We aimed to determine the association between change in plasma VEGF-A levels and the efficacy of chemotherapy combined with anti-PD-1/PD-L1 antibodies (chemo-PD1) in non-small cell lung cancer (NSCLC) patients., Methods: We included NSCLC patients treated with chemo-PD1. Plasma VEGF-A levels were measured at baseline (Pre) and days 7 (D7) and 14 (D14) after the initiation of chemo-PD1. Continuous VEGF-A decrease was determined by comparing Pre with the median value of maximum change rate of posttreatment VEGF-A as cutoff. Patients whose change rates of VEGF-A at both D7 and D14 were consistently lower than the cutoff value were classified into the VEGF-A decrease group, whereas those whose VEGF-A at D7 or D14 were higher than the cutoff level were classified into the VEGF-A no-decrease group. The primary outcome was progression-free survival (PFS)., Results: A total of 32 patients were evaluated. The median Pre VEGF-A levels was 49 (range, 13-257). The median change rate of VEGF-A at D7 and D14 was -25.6% (range, -77.5-376.9) and -42.3% (range, -100-138.5) respectively. The cutoff value of posttreatment VEGF-A change rate was -9.3%. The PFS was significantly longer in the VEGF-A decrease group than that in the VEGF-A no-decrease group (median, not reached vs 2.4 months; p = 0.017)., Conclusions: Continuous decrease of plasma VEGF-A levels during treatment may be associated with the efficacy of chemo-PD1., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Rearranged during transfection (RET)-rearranged non-small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented., Patients and Methods: We identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics., Results: In 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%)., Conclusion: Advanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The survival of patients with EGFR mutation-positive lung cancer has dramatically improved since the introduction of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Recently, osimertinib showed significantly prolonged progression-free survival than first-generation EGFR-TKI in first-line treatment, suggesting that a paradigm change that would move osimetinib to first-line treatment is indicated. We performed N-ethyl-N-nitrosourea (ENU) mutagenesis screening to uncover the resistant mechanism in first- and second-line osimertinib treatment., Methods: Ba/F3 cells harboring EGFR activating-mutation with or without secondary resistant mutation were exposed to ENU for 24 hours to introduce random mutations and selected with gefitinib, afatinib, or osimertinib. Mutations of emerging resistant cells were assessed., Results: The resistance of T790M and C797S to gefitinib and osimertinib, respectively, was prevalent in the mutagenesis screening with the Ba/F3 cells harboring activating-mutation alone. From C797S/activating-mutation expressing Ba/F3, the additional T790M was a major resistant mechanism in gefitinib and afatinib selection and the additional T854A and L792H were minor resistance mechanisms only in afatinib selection. However, the additional T854A or L792H mediated resistance to all classes of EGFR-TKI. Surprisingly, no resistant clone due to secondary mutation emerged from activating-mutation alone in the gefitinib + osimertinib selection., Conclusions: We showed the resistance mechanism to EGFR-TKI focusing on first- and second-line osimertinib using ENU mutagenesis screening. Additional T854A and L792H on C797S/activating-mutation were found as afatinib resistance and not as gefitinib resistance. Thus, compared to afatinib, the first-generation EGFR-TKI might be preferable as second-line treatment to C797S/activating-mutation emerging after first-line osimertinib treatment., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)