Abstract A91: Activating EGFR mutation, G719A, was selected in the c-MET amplified NSCLC-PDX-LU1901 during the treatments by c-MET inhibitors and the resistance development.

Abstract

Abstract We previously described the establishment of an Asian NSCLC patient derived xenograft (PDX), LU1901 (large cell carcinoma, or LCC), from a surgically removed patient tumor tissue, along with large panel of other NSCLC-PDX (1). LU1901 was found to have amplified c-MET gene and responded to multiple c-MET inhibitors, including crizotinib (near-complete regression) (1). Interestingly, we recently also observed that the TKI treatments, including crizotinib, induced rapid development of resistance against the TKIs (LU1902, LU1903) (2). However, efforts so far have yet to demonstrate mechanism causing the induced resistance (2). We are currently investigating many aspects of the resistant tumors, including histopathology and molecular features, e.g., further c-MET mutation, c-MET activation status, and inhibition by c-MET-TKI, etc. By hotspot sequencing of EGFR gene of LU1901 and LU1903 recently (Sanger Method), we found a known activating mutation, G719A in exon 18, was selected during the treatment that was also accompanied by the c-MET TKI resistance development. G719A has been found in small subset of patients (∼3%) (3), and has been associated with increased sensitivity to EGFR-TKIs (4), suggesting it could be a new driver mutation gained in resistant LU1903. At present, our working hypothesis is that the selection of G719A mutation of EGFR rendered LU1903 resistant to c-MET-TKI. We have planned further experiments to verify this hypothesis. As a first step, we performed RNAseq of the TKI-sensitive parental LU1901, and found that G719A seemed to already exist, although at much lower frequency as compared to wild type allele at this location. This preliminary results suggests that G719A is a pre-exist mutation in a small subset of LU1901 tumor cells which was rapidly selected out during c-MET TKI treatment. Our current working hypothesis is that this selection could be responsible for the resistance development. If our working hypothesis is eventually proven, it will provide a new important mechanism for the development of c-MET TKI resistancy that can occur in the clinic during MET based therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A91. Citation Format: Mengmeng Yang, Jie Cai, Sheng Guo, Shijun Yu, Wubin Qian, Xiaoming Song, Youzhu Wang, Jean-Pierre Wery, Henry Li. Activating EGFR mutation, G719A, was selected in the c-MET amplified NSCLC-PDX-LU1901 during the treatments by c-MET inhibitors and the resistance development. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A91.