Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR
Metrics: PDF 2266 views | Full Text 4005 views | ?
Hengyu Lu1, Chen Liu1, Hung Huynh2, Thi Bich Uyen Le2, Matthew J. LaMarche3, Morvarid Mohseni1, Jeffrey A. Engelman1, Peter S. Hammerman1, Giordano Caponigro1 and Huai-Xiang Hao1
1 Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, Massachusetts, USA
2 Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, Singapore
3 Novartis Institutes for Biomedical Research, Global Discovery Chemistry, Cambridge, Massachusetts, USA
|Huai-Xiang Hao,||email:||[email protected]|
Keywords: SHP2; FGFR; resistance; feedback activation
Received: October 17, 2019 Accepted: December 29, 2019 Published: January 21, 2020
SHP2 mediates RAS activation downstream of multiple receptor tyrosine kinases (RTKs) and cancer cell lines dependent on RTKs are in general dependent on SHP2. Profiling of the allosteric SHP2 inhibitor SHP099 across cancer cell lines harboring various RTK dependencies reveals that FGFR-dependent cells are often insensitive to SHP099 when compared to EGFR-dependent cells. We find that FGFR-driven cells depend on SHP2 but exhibit resistance to SHP2 inhibitors in vitro and in vivo. Treatment of such models with SHP2 inhibitors results in an initial decrease in phosphorylated ERK1/2 (p-ERK) levels, however p-ERK levels rapidly rebound within two hours. This p-ERK rebound is blocked by FGFR inhibitors or high doses of SHP2 inhibitors. Mechanistically, compared with EGFR-driven cells, FGFR-driven cells tend to express high levels of RTK negative regulators such as the SPRY family proteins, which are rapidly downregulated upon ERK inhibition. Moreover, over-expression of SPRY4 in FGFR-driven cells prevents MAPK pathway reactivation and sensitizes them to SHP2 inhibitors. We also identified two novel combination approaches to enhance the efficacy of SHP2 inhibitors, either with a distinct site 2 allosteric SHP2 inhibitor or with a RAS-SOS1 interaction inhibitor. Our findings suggest the rapid FGFR feedback activation following initial pathway inhibition by SHP2 inhibitors may promote the open conformation of SHP2 and lead to resistance to SHP2 inhibitors. These findings may assist to refine patient selection and predict resistance mechanisms in the clinical development of SHP2 inhibitors and to suggest strategies for discovering SHP2 inhibitors that are more effective against upstream feedback activation.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.