Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models
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Michael S. Lee1,2, Timothy L. Helms3, Ningping Feng5, Jason Gay5, Qing Edward Chang5, Feng Tian4, Ji Y. Wu4, Carlo Toniatti5,6, Timothy P. Heffernan5,6, Garth Powis7, Lawrence N. Kwong3, Scott Kopetz4
1Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
3Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
5Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA
6Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA
7Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
Lawrence N. Kwong, email: email@example.com
Scott Kopetz, email: firstname.lastname@example.org
Keywords: KRAS, NRAS, MEK inhibitor, CDK4/6 inhibitor
Received: December 28, 2015 Accepted: April 16, 2016 Published: May 04, 2016
Purpose: Though 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.
Results: The 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 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 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.
Conclusions: 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.
Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.
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