Faculty, Staff and Student Publications

Publication Date

9-16-2022

Abstract

UNLABELLED: KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib in a safety lead-in confirmed safety and provided preliminary evidence of activity. Prolonged treatment in PDX models resulted in feedback activation of receptor tyrosine kinases and acquired resistance, which was reversed with a SHP2 inhibitor. These results highlight the clinical potential of this combination in colorectal cancer, along with the utility of PDX-based co-clinical trial platforms for drug development.

SIGNIFICANCE: This co-clinical trial of combined MEK-CDK4/6 inhibition in RAS mutant colorectal cancer demonstrates therapeutic efficacy in patient-derived xenografts and safety in patients, identifies biomarkers of response, and uncovers targetable mechanisms of resistance.

Keywords

Cell Line, Tumor, Colorectal Neoplasms, Cyclin-Dependent Kinase 4, Humans, Mitogen-Activated Protein Kinase Kinases, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins p21(ras), Tyrosine, Xenograft Model Antitumor Assays

DOI

10.1158/0008-5472.CAN-22-0198

PMID

35913398

PMCID

PMC9478530

PubMedCentral® Posted Date

8-1-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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