Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models

Lee, Michael S.; Helms, Timothy L.; Feng, Ningping; Gay, Jason; Chang, Qing Edward; Tian, Feng; Wu, Ji Y.; Toniatti, Carlo; Heffernan, Timothy P.; Powis, Garth; Kwong, Lawrence N.; Kopetz, Scott

doi:10.18632/oncotarget.9153

Cited by 123Colorectal Cancer Treatments and StudiesMelanoma and MAPK PathwaysProtein Kinase Regulation and GTPase Signaling

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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Lee, Michael S., Helms, Timothy L., Feng, Ningping, Gay, Jason, Chang, Qing Edward, Tian, Feng, Wu, Ji Y., Toniatti, Carlo +4 more·2016·Oncotarget

DOI 10.18632/oncotarget.9153PMC PMC5129956

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Abstract

// Michael S. Lee 1, 2 , Timothy L. Helms 3 , Ningping Feng 5 , Jason Gay 5 , Qing Edward Chang 5 , Feng Tian 4 , Ji Y. Wu 4 , Carlo Toniatti 5, 6 , Timothy P. Heffernan 5, 6 , Garth Powis 7 , Lawrence N. Kwong 3 , Scott Kopetz 4 1 Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 2 Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 3 Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Sanford-Burnham Medical Research Institute, La Jolla, CA, USA Correspondence to: Lawrence N. Kwong, email: lkwong@mdanderson.org Scott Kopetz, email: skopetz@mdanderson.org Keywords: KRAS, NRAS, MEK inhibitor, CDK4/6 inhibitor Received: December 28, 2015 Accepted: April 16, 2016 Published: May 04, 2016 ABSTRACT 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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The combination of CDK4/6 inhibitors with MEK inhibition has been shown to synergistically reduce the growth of KRAS-mutant CRC both in vitro and in vivo.
“The combination of CDK 4/6 inhibitors with MEK inhibition has been shown to synergistically reduce the growth of KRAS-mutant CRC both in vitro and in vivo [82].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [82]

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Authors: Lee, M. S., Helms, T. L., Feng, N., Gay, J., Chang, Q. E., Tian, F., Wu, J. Y., Toniatti, C., Heffernan, T. P., Powis, G., Kwong, L. N., & Kopetz, S.
Affiliations: University of North Carolina at Chapel Hill (US)
The University of Texas MD Anderson Cancer Center (US)
Sanford Burnham Prebys Medical Discovery Institute (US)
ORCID: Lee, Michael S.
Helms, Timothy L.
Feng, Ningping
Chang, Qing Edward
Toniatti, Carlo
Heffernan, Timothy P.
Powis, Garth
Kwong, Lawrence N.
Kopetz, Scott
Venue: Oncotarget
Publisher: Impact Journals, LLC
Published: 2016-05-04
Volume: 7
Issue: 26
Pages: 39595-39608
ISSN: 1949-2553 (ISSN-L)
DOI: 10.18632/oncotarget.9153
PMC: PMC5129956
OpenAlex: W2345781825
Cited by: 123
References: 70
Citations by year: 2026: 9 · 2025: 14 · 2024: 6 · 2023: 10 · 2022: 14 · 2021: 18 · 2020: 16 · 2019: 11 · 2018: 8 · 2017: 13 · 2016: 4
FWCI: 6.47
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: cc-by
Locations: Oncotarget (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (KL2TR000370)
National Cancer Institute (R21CA185504, R01CA172670, P50CA093459)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: MEK inhibitors, CDK4/6 inhibitors, KRAS-mutant colorectal cancer, combination therapy, cyclin D, S6 phosphorylation, Ki-67, senescence, patient-derived xenografts, tumor regression, drug resistance, MEK inhibitor resistance, cell cycle entry, apoptosis, senescence-associated secretory phenotype
MeSH terms: Animals, Antineoplastic Agents, Clinical Trials as Topic, Disease Models, Animal, Female, Humans, Mice, Nude, Mutation, Neoplasm Transplantation, Phosphorylation, Piperazines, Pyridines, Genes, ras, Colorectal Neoplasms, Treatment Outcome, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase Kinase 1, Cell Proliferation, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice

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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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