Hao, Huaixiang, Wang, Hongyun, Liu, Chen, Kovats, Steven, Velazquez, Roberto, Lu, Henry, Pant, Bhavesh, Shirley, Matthew, Meyer, Matthew, Pu, Minying, Lim, Joanne, Fleming, Michael, Alexander, Leigh Ann, Farsidjani, Alireza, LaMarche, Matthew, Moody, Susan, Silver-Brown, Serena, Caponigro, Giordano, Stuart, Darrin, Abrams, Tinya, Hammerman, Peter, Williams, Juliet, Engelman, Jeffrey, Goldoni, Silvia and Mohseni, Mori (2019) Tumor intrinsic efficacy by SHP2 and RTK inhibitors in KRAS mutant cancers. Molecular cancer therapeutics.

Abstract

KRAS, an oncogene mutated in nearly one-third of human cancers, remains a pharmacological challenge for direct inhibition except in the case of recent advances in selective inhibitors targeting the KRAS-G12C variant. Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, is effective in treating KRAS mutant cancer cell lines in vitro and in vivo. In vitro, sensitization of KRAS-driven cancers towards the allosteric SHP2-inhibitor, SHP099, is revealed when cells are grown as multicellular spheroids and correlates with activity in mouse models but is not apparent in standard 2D cell culture conditions. Interrogation of the MAPK pathway in SHP099 treated KRAS-mutant cancer models suggested relevance of both MAPK and non-MAPK pathway dependent mechanisms correlating with SHP099 sensitivity as phospho-ERK and DUSP6 modulation were equivalent in 2D, 3D and in vivo models despite differences in compound sensitivity. We demonstrate that efficacy is tumor-intrinsic due to the lack of anti-angiogenic activity of SHP099 and recapitulation of efficacy by genetic depletion of SHP2 in cancer cells, suggesting a dependence on RTK signaling upstream of RAS. Furthermore, KRAS mutants with low intrinsic GTP hydrolysis, e.g. KRAS-G13D and Q61H, also are sensitive to SHP099 in vivo. Taken together, these data reveal that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, and provide a new therapeutic strategy for treating KRAS mutant cancers with SHP2 inhibitors.

Item Type:	Article
Date Deposited:	19 Sep 2019 00:45
Last Modified:	19 Sep 2019 00:45
URI:	https://oak.novartis.com/id/eprint/37698