SHP2 Inhibition Overcomes RTK-Mediated Pathway Reactivation in KRAS-Mutant Tumors Treated with MEK Inhibitors
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Published on: July 17, 2020
Hengyu Lu1, Chen Liu1, Roberto Velazquez1
1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
Abstract:
FGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with the MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTK) 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 an 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 that 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.
Insights
Receptor tyrosine kinases (RTKs) can activate feedback loops in KRAS-mutant cancers treated with MEK inhibitors. Combining SHP2 and MEK inhibitors shows promise for treating these cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- MEK inhibitors can trigger compensatory feedback activation of FGFR1 in KRAS-mutant cancers.
- The role of other receptor tyrosine kinases (RTKs) in this feedback mechanism remains largely unexplored.
Purpose of the Study:
- To investigate the contribution of various RTKs to feedback activation of phospho-MEK upon MEK inhibition in KRAS-mutant cancer cell lines.
- To evaluate the therapeutic potential of combining SHP2 and MEK inhibitors for KRAS-mutant cancers.
Main Methods:
- Profiling of KRAS-mutant cancer cell lines to assess RTK contribution to feedback activation using an SHP2 inhibitor (SHP099).
- Investigating the role of KRAS variants (mutant and wild-type) in mediating feedback activation.
- Assessing the in vitro and in vivo efficacy of combining SHP099 and MEK inhibitors.
Main Results:
- RTK-driven feedback activation is prevalent in KRAS-mutant cancers, involving EGFR, FGFR, and MET, though less pronounced in G13D variants.
- This feedback is mediated by mutant KRAS (G12C, G12D, G12V) and significantly by wild-type KRAS.
- Combination therapy with SHP099 and MEK inhibitors demonstrated synergistic effects on inhibiting cancer cell proliferation.
Conclusions:
- Feedback activation of RTKs is a common compensatory mechanism in KRAS-mutant cancers under MEK inhibition.
- SHP2 inhibition, in combination with MEK inhibitors, offers a promising therapeutic strategy for KRAS-mutant cancers.
- Further clinical exploration of combined SHP2 and MAPK pathway inhibition is warranted.
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