Abstract 1007: SHP2 inhibition restores sensitivity to ALK inhibition in resistant ALK-rearranged non-small cell lung cancer (NSCLC)

Despite development of highly potent and selective inhibitors (e.g., ceritinib, alectinib, lorlatinib) targeting anaplastic lymphoma kinase (ALK), resistance invariably develops and limits the efficacy of these inhibitors in the clinic. The major classes of resistance are on-target genetic alterations (e.g., secondary ALK kinase domain mutations) and activation of alternative or bypass signaling pathways. While most patients are responsive to sequential treatment with two or more ALK inhibitors, ALK-independent resistance eventually emerges and leads to failure of further ALK-directed monotherapy. We used a synthetic lethal pooled shRNA screen to discover loss-of-function events that could sensitize resistant patient-derived cell lines to ALK inhibition. In addition to identifying known bypass targets such as FGFR, EGFR and SRC, we also identified PTPN11 (which encodes SHP2, a non-receptor protein tyrosine phosphatase that modulates signaling downstream of growth factor receptors) as a common hit shared by cell lines exhibiting different mechanisms of bypass activation. In parallel with the shRNA screen, we also performed a high throughput combination compound screen in the same patient-derived models, and identified activation of the same bypass signaling pathways. We showed that the highly potent and selective small-molecule SHP2 inhibitor SHP099 could sensitize resistant cell lines to ALK inhibition. In biochemical studies, co-targeting of ALK and SHP2 overcame resistance mediated by ALK-independent bypass mechanisms by decreasing RAS-GTP loading potential of cells and inhibiting phospho-ERK rebound. These results suggest that dual ALK and SHP2 inhibition may represent a new therapeutic strategy for ALK-positive patients, whose lung cancers have evolved ALK-independent mechanisms of resistance, including activation of bypass signaling pathways. Citation Format: Leila Dardaei, Hui Qin Wang, Paul Fordjour, Manrose Singh, Grainne Kerr, Satoshi Yoda, Jinsheng Liang, Yichen Cao, Yan Chen, Justin F. Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T. Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H. DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Cyril H. Benes, Alice T. Shaw, Aaron N. Hata, Fang Li, Jeffrey A. Engelman. SHP2 inhibition restores sensitivity to ALK inhibition in resistant ALK-rearranged non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1007. doi:10.1158/1538-7445.AM2017-1007