In-frame deletions within exon 19 (Ex19Del) and the Leu858Arg mutation within exon 21 (L858R) are the two most common oncogenic EGFR mutations found in non-small cell lung cancer (NSCLC). Currently, there is little data differentiating Ex19Del from L858R, and patients whose tumors harbor Ex19Del and L858R are approached similar in clinic when choosing EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, resistance mutations may emerge against all classes of EGFR TKIs, including osimertinib. Recently, G724S has been identified as a novel mutation which is selected in osimertinib resistant tumors. Interestingly, in a large genomic profile database of NSCLC patient samples we found that G724S co-occurs preferentially with Ex19Del (15/19 G724S cases) but not with L858R (0/19 G724S cases). We further combined in silico and in vitro investigations to demonstrate the mechanism of G724S mutation confers resistance to TKIs in an oncogenic variant-dependent manner. Our in silico investigations showed evidence of reduced stability of the osimertinib-bound G724S/Ex19Del complex but not the osimertinib-bound G724S/L858R complex. G724S/Ex19Del-transduced cells are resistant to osimertinib treatment in vitro, while G724S/L858R-transduced cells are sensitive to osimertinib treatment. These results suggest G724S/Ex19Del may emerge under selective pressure from EGFR TKIs, and the underlying oncogenic profile of EGFR can influence the development of drug resistance mutations. Our results have potential direct implications for the treatment of patients with EGFR-mutant NSCLC.

Citation Format: Yunkai Zhang, Benjamin P. Brown, David Westover, Yingjun Yan, Huan Qiao, Vincent Huang, Zhenfang Du, Jarrod A. Smith, Jeffrey S. Ross, Vincent A. Miller, Siraj Ali, Lyudmila Bazhenova, Alexa B. Schrock, Jens Meiler, Christine M. Lovly. On-target resistance to mutant selective EGFR inhibitors develops in an allele-specific manner dependent on the original EGFR activating mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 930.