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Ref Type Journal Article
PMID (35913398)
Authors Sorokin AV, Kanikarla Marie P, Bitner L, Syed M, Woods M, Manyam G, Kwong LN, Johnson B, Morris VK, Jones P, Menter DG, Lee MS, Kopetz S
Title Targeting RAS mutant colorectal cancer with dual inhibition of MEK and CDK4/6.
Abstract Text KRAS and NRAS mutations occur in 45% of colorectal cancers (CRC), 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 metastatic CRC patients 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 CRC, along with the utility of PDX-based co-clinical trial platforms for drug development.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61K colorectal cancer sensitive Palbociclib + Trametinib Preclinical - Pdx Actionable In a preclinical study, combination treatment with Ibrance (palbociclib) and Mekinist (trametinib) led to greater inhibition of tumor growth than either agent alone in a patient-derived xenograft (PDX) model of colorectal cancer harboring NRAS Q61K (PMID: 35913398). 35913398