Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR.

Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR. Oncotarget. 2020 Jan 21;11(3):265-281 Authors: Lu H, Liu C, Huynh H, Le TBU, LaMarche MJ, Mohseni M, Engelman JA, Hammerman PS, Caponigro G, Hao HX Abstract 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 di...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research