Abstract 1864: Generation of a triple-mutation (T790M/C797S/L858R) NSCLC cell line for relevant drug discovery and development

Epidermal Growth Factor Receptor (EGFR) overexpression is observed in a large subset of patients with non-small-cell lung cancer (NSCLC) and correlated with poor prognosis. Current approved treatment for EGFR mutation-positive NSCLC has been revolutionized with three generations of EGFR tyrosine kinase inhibitors (TKIs): the first- and second-generation TKIs, such as gefitinib, erlotinib and afatinib, selectively targeting EGFR activating mutations existing in exon 19 and 21; and the third-generation EGFR-wild-type sparing, irreversible activating mutations/T790M inhibitor, osimertinib. Patients with somatic activating mutations in the EGFR gene have dramatic response initially, but would eventually develop resistance to these TKIs. One leading evidence of osimertinib resistance is mediated by occurrence of the point mutation C797S. There are no effective therapeutic strategies to overcome this triple-mutation (activating mutations/T790M/C797S) mediated resistance. Therefore, it is urged to develop new drug to target this particular mutant. There is still lack of triple-mutation in vitro model for the new generation drug discovery. In this study, a triple-mutation NSCLC model was generated in the NCI-H1975 lung cancer cell line, which harbors other naturally occurring EGFR genomic aberrations - double-mutation (T790M/L858R) - inherent in NSCLC. We utilized the CRISPR/Cas9 genome editing tool to target endogenous loci in human NSCLC cell line NCI-H1975 and created the intend point mutation, resulting in the triple mutation cell line (T790M/C797S/L858R). Further phenotypic analysis demonstrated that the triple-mutation cell line was resistant to the third generation inhibitors in contrast to the parental double-mutation cell line. This newly developed triple-mutation lung cancer cell line provided a very useful tool for oncology drug discovery for NSCLC. Citation Format: Huiying Ma, Peixue Li, Peiran Zhang, Fuyun Sun, Qing Lin. Generation of a triple-mutation (T790M/C797S/L858R) NSCLC cell line for relevant drug discovery and development [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 1864.