A selective, allosteric SHP2 inhibitor reduces tumor growth via suppression of RAS–ERK signaling.

  • Major finding: A selective, allosteric SHP2 inhibitor reduces tumor growth via suppression of RAS–ERK signaling.

  • Concept: Allosteric inhibition locks the SHP2 phosphatase in an autoinhibitory conformation.

  • Impact: Pharmacologic inhibition of SHP2 may have therapeutic potential in patients with RTK-driven tumors.

Amplification of receptor tyrosine kinases (RTK) such as EGFR or FGFR is found in several types of cancer. SHP2 is a phosphatase activated by interacting with the RTK through simultaneous binding to the N-terminal and C-terminal SH2 domains, thereby releasing autoinhibition and making the active site available. Suppressing SHP2 activity reduces tumor growth, but developing small molecules to target the catalytic site of protein tyrosine phosphatases (PTP) has proven challenging, suggesting the potential for allosteric inhibitors. Chen and colleagues identified SHP2 as a potential cancer therapeutic target in an shRNA screen targeting 7,500 genes across 250 cancer cell lines. Cell lines dependent on RTK signaling were sensitive to SHP2 depletion resulting in reduced cell growth and ERK activation, whereas cells dependent on KRAS, NRAS, or BRAF were not. Further, overexpression of constitutively active KRASG12V in SHP2-dependent cells restored phospho-ERK levels and reduced the dependence on SHP2, suggesting that RAS/RAF-mutant cells may not be sensitive to SHP2 inhibition. A screen of 100,000 compounds to find specific, allosteric SHP2 inhibitors identified SHP099. Solving the crystal structure of SHP099 in complex with SHP2 revealed that SHP099 bound to the interface between the N- and C-terminal SH2 domains and the PTP domain, consistent with allosteric activity via stabilization of the inactive conformation, locking SHP2 in the autoinhibited state. In line with the results of the shRNA screen, SHP099 inhibited the growth of a panel of hematopoietic cancer cell lines with known oncogenic tyrosine kinase alterations, and colorectal cancer cells that were sensitive to EGFR inhibition, but not RAS- or BRAF-mutant hematopoietic or colorectal cancer cells. Additionally, SHP099 was effective in reducing phospho-ERK and suppressing tumor growth in vivo, and was orally bioavailable and well tolerated in mice. Taken together, these findings identify a potential inhibitor of SHP2 and suggest that allosteric inhibition of SHP2 may be an effective therapeutic option in RTK-driven tumors.

Chen YP, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 2016;535:148–52.