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.

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©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.

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Supplementary data

Supplementary Figure 1

Schematic illustration of MEKi-induced MAPK pathway feedback activation, SHP099 dose-dependent reduction of p-MEK induction by MEKi, and MEKi-induced p-AKT levels.

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Supplementary Figure 2

Validation of HRAS/NRAS double knock-out clones and the contribution of mutant KRAS to the feedback activation in NCI-H358 and MIA PaCa-2.

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Supplementary Figure 3

Evaluation of the in vitro synergy in anti-proliferation and the MAPK pathway suppression of MEK and SHP2, PI3K, or RTK inhibitors.

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Supplementary Figure 4

Evaluation of the in vivo combination benefit and the MAPK pathway suppression of MEK and SHP2 inhibitors in MIA PaCa-2 xenograft and a colon cancer PDX model.

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Supplementary Figure 5

Changes in phospho-SHP2 levels following MEKi treatment in studied KRAS mutant lines.

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Supplementary Table 1

A list of KRAS mutant cell lines in the study with lineages, zygosity determined by RNAseq, and percentages of p-MEK reduction by 5 micromolar SHP099 in the MEKi combination group.

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Supplementary Table 2

Quantification of p-MEK and tubulin levels and percentages of p-MEK reduction in the MEKi combination group normalized to tubulin in all cell lines tested.

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Supplementary Table 3

mRNA levels (TPM, transcripts per million reads in RNAseq) of SHP2, RTKs, and their ligands in all cell lines tested.

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