Abstract
PurposeThough the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo.ResultsThe combination of MEK and CDK4/6 inhibitors synergistically inhibited cancer cell growth in vitro and caused tumor regression in vivo in cell line and patient-derived xenograft models. Combination therapy markedly decreased levels of phosphorylated ribosomal protein S6 both in vitro and in vivo and decreased Ki67 staining in vivo.Experimental DesignWe performed in vitro proliferation, colony formation, apoptosis, and senescence assays, and Western blots, on a panel of 11 KRAS mutant CRC cell lines treated with the MEK inhibitor MEK162, the CDK4/6 inhibitor palbociclib, or the combination. We also treated 4 KRAS mutant CRC cell line and patient-derived xenografts with the MEK inhibitor trametinib, the CDK4/6 inhibitor palbociclib, or the combination, and performed immunohistochemical and reverse phase protein array analysis.ConclusionsCombined inhibition of both MEK and CDK4/6 is effective in preclinical models of KRAS mutant CRC and justifies a planned phase II clinical trial in patients with refractory KRAS-mutant CRC.Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.
Highlights
Somatic activating mutations in KRAS or NRAS are present in up to 52% of colorectal cancer (CRC) [1, 2], causing constitutive activation of the RAF/ MEK/ERK signaling pathway independent of upstream receptor tyrosine kinases like the epidermal growth factor receptor (EGFR)
Experimental Design: We performed in vitro proliferation, colony formation, apoptosis, and senescence assays, and Western blots, on a panel of 11 KRAS mutant CRC cell lines treated with the MEK inhibitor MEK162, the CDK4/6 inhibitor palbociclib, or the combination
We treated 4 KRAS mutant CRC cell line and patient-derived xenografts with the MEK inhibitor trametinib, the CDK4/6 inhibitor palbociclib, or the combination, and performed immunohistochemical and reverse phase protein array analysis. Combined inhibition of both MEK and CDK4/6 is effective in preclinical models of KRAS mutant CRC and justifies a planned phase II clinical trial in patients with refractory KRAS-mutant CRC
Summary
Somatic activating mutations in KRAS or NRAS are present in up to 52% of colorectal cancer (CRC) [1, 2], causing constitutive activation of the RAF/ MEK/ERK signaling pathway independent of upstream receptor tyrosine kinases like the epidermal growth factor receptor (EGFR). These mutations are known predictive biomarkers of resistance in metastatic CRC to anti-EGFR therapy, such as cetuximab or panitumumab, and patients whose tumors harbor KRAS or NRAS mutations have fewer therapeutic options. Rational drug combinations with MEK inhibitors, potentially with agents that target downstream effectors of ERK, are likely necessary to overcome compensatory responses to MEK inhibitors
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