Abstract 6223: Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models

Abstract Osimertinib (AZD9291) is the first-line treatment for EGFR-mutated NSCLC; however, the majority of patients inevitably develop resistance due to de novo genomic abnormalities, such as C797S mutation, EGFR exon 20 insertion, MET amplification and other unknown mechanisms. Hence, effective therapies to overcome acquired resistance are urgently needed. Inhibition of BCL-2/BCL-xL has been reported to enhance apoptosis in EGFR-TKI resistant cells with low sensitivity to EGFR inhibition. In this study, we evaluated whether the combination of a dual BCL-2/BCL-xL inhibitor APG-1252 and chemotherapeutics could overcome osimertinib resistance in preclinical xenograft models. First, EGFR C797S mutation was introduced to human NCI-H1975 NSCLC cells to construct an NCI-H1975-C797S resistant cell line using CRISPR technology. NCI-H1975-C797S derived-xenografts were treated with APG-1252, cisplatin/docetaxel or their combinations. Combination therapy with APG-1252 and cisplatin or docetaxel exhibited synergistic antitumor activity. APG-1252 plus docetaxel combination achieved 100% tumor partial regression (PR). Similar results were demonstrated in a patient-derived xenograft (PDX) tumor model derived from an osimertinib-resistant NSCLC patient harboring 19del-T790M-C797S mutations. Furthermore, the combinations also exhibited enhanced antitumor activity in an osimertinib-resistant PDX model that the resistant mechanism remained unknown. In summary, our results suggest that the combination treatment with APG-1252 and chemotherapeutics can overcome acquired resistance to osimertinib and the combination deserves further clinical evaluations. Citation Format: Ran Tao, Guangfeng Wang, Douglas D. Fang, Guoqin Zhai, Yuanbao Li, Jing Lv, Miaoyi Wu, Yangfeng Ge, Feifei Zhang, Danyi Wen, Dajun Yang, Yifan Zhai. Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6223.