SHP2 inhibition overcomes RTK-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors

FGFR1 was recently shown to be activated as part of a extent in those harboring the G13D variant, and involves compensatory response to prolonged treatment with the MEK several RTKs, including EGFR, FGFR, and MET. We further inhibitor trametinib in several KRAS-mutant lung and pan-demonstrate that this pathway feedback activation is mediated creatic cancer cell lines. We hypothesize that other receptor through mutant KRAS, at least for the G12C, G12D, and G12V tyrosine kinases (RTK) are also feedback-activated in this variants, and wild-type KRAS can also contribute significantly context. Herein, we profile a large panel of KRAS-mutant to the feedback activation. Finally, SHP099 and MEK inhibi-cancer cell lines for the contribution of RTKs to the feedback tors exhibit combination benefits inhibiting KRAS-mutant activation of phospho-MEK following MEK inhibition, using cancer cell proliferation in vitro and in vivo. These findings an SHP2 inhibitor (SHP099) that blocks RAS activation medi-provide a rationale for exploration of combining SHP2 and ated by multiple RTKs. We find that RTK-driven feedback MAPK pathway inhibitors for treating KRAS-mutant cancers in activation widely exists in KRAS-mutant cancer cells, to a less the clinic.