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

Lu, Henry and Liu, Chen and Velazquez, Roberto and Wang, Hongyun and Dunkl, Lukas and Kazic-Legueux, Malika and Haberkorn, Anne and Billy, Eric and Manchado Robles, Eusebio and Brachmann, Saskia and Moody, Susan and Engelman, Jeffrey and Hammerman, Peter and Caponigro, Giordano and Mohseni, Mori and Hao, Huaixiang (2019) SHP2 inhibition overcomes RTK-mediated pathway re-activation in KRAS mutant tumors treated with MEK inhibitors. Molecular cancer therapeutics. ISSN 1538-8514


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

Item Type: Article
Date Deposited: 31 May 2019 00:45
Last Modified: 31 May 2019 00:45


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