Abstract LB-259: FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition

Abstract

Abstract Introduction: The non-receptor protein tyrosine phosphatase SHP2 mediates RAS activation downstream of various receptor tyrosine kinases (RTKs). Cancer cell lines dependent on RTK signaling are generally sensitive to SHP2 genetic knockdown but differ widely in their sensitivity to allosteric SHP2 inhibitors such as SHP099. A recent report suggested that FGFR can drive resistance to MAPK inhibitors independently of SHP2. We sought to understand the molecular basis of differential sensitivity to allosteric SHP2 inhibitors when SHP2 is activated by different RTKs, particularly FGFR versus EGFR. Experimental procedures: We profiled a panel of cancer cell lines driven by various wild-type FGFR activation (receptor amplification or autocrine ligand mediated) for their sensitivity to SHP099 and characterized MAPK pathway inhibition at various time points and SHP099 doses, in comparison with EGFR-driven cell lines. We also compared the inhibitory effects of SHP099 on FGFR- and EGFR-mediated pathway feedback activation in response to MEK inhibitor treatment. Results: We find FGFR-driven cell lines are often more resistant to SHP099 compared to EGFR-driven cell lines. Those SHP099-resistant FGFR-driven cell lines were sensitive to SHP2 knockdown and SHP099 inhibited p-ERK in those cells at earlier time points. However, p-ERK quickly rebounded after SHP099 treatment, which was not observed with FGFR inhibitors and can be attenuated with high concentrations of SHP099. Consistently, FGFR-driven MAPK pathway feedback activation following treatment with MEK inhibitor was also more resistant to SHP099 compared to EGFR-driven feedback activation. Additional studies are being performed in isogenic cell lines for direct comparison. Conclusions: Our findings suggest that many FGFR-driven cell lines are dependent on SHP2 but are intrinsically resistant to allosteric SHP2 inhibition, compared to EGFR-driven cell lines. FGFR-driven cells tend to have a quick p-ERK rebound following initial pathway inhibition by SHP099, which is mediated by the feedback activation of FGFR. The feedback activated FGFR likely efficiently promotes the open conformation of SHP2 and causes resistance to allosteric SHP2 inhibitors. For certain FGFR-driven cancers, SHP2 inhibitor combinations such as with MAPK inhibitors might be needed for sustained efficacy. Citation Format: Huaixiang Hao, Hengyu Lu, Chen Liu, Matthew LaMarche, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro. FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition [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 LB-259.