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Ref Type Journal Article
PMID (39148328)
Authors Wu J, Wang J, O'Connor TN, Tzetzo SL, Gurova KV, Knudsen ES, Witkiewicz AK
Title Separable Cell Cycle Arrest and Immune Response Elicited through Pharmacological CDK4/6 and MEK Inhibition in RASmut Disease Models.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 23 12 2024 Dec 03 1801-1814 Mol Cancer Ther
URL
Abstract Text The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth. CRISPR-mediated RB1 depletion resulted in a decreased response to CDK4/6 and MEK inhibition, which was validated in both cell culture and xenograft models. Beyond its cell cycle inhibitory effects, pathway enrichment analysis revealed the robust activation of interferon pathways upon CDK4/6 and MEK inhibition. This induction of gene expression was associated with the upregulation of retroviral elements. The TANK-binding kinase 1 inhibitor GSK8612 selectively blocked the induction of interferon-related genes induced by palbociclib and trametinib treatment and highlighted the separable epigenetic responses elicited by combined CDK4/6 and MEK inhibition. Together, these findings provide key mechanistic insights into the therapeutic potential of CDK4/6 and MEK inhibition in soft tissue sarcomas.

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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 fibrosarcoma sensitive Palbociclib + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) and Ibrance (palbociclib) combination treatment synergistically inhibited proliferation and induced cell cycle arrest of a fibrosarcoma cell line harboring NRAS Q61K in culture and inhibited tumor growth in a cell line xenograft model (PMID: 39148328). 39148328