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Ref Type Journal Article
PMID (24795392)
Authors Dickson MA
Title Molecular pathways: CDK4 inhibitors for cancer therapy.
Journal Clinical cancer research : an official journal of the American Association for
Vol 20
Issue 13
Date 2014 Jul 1
URL
Abstract Text Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G1-S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16-CDK4-cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs.

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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
RB1 positive Advanced Solid Tumor predicted - sensitive Ribociclib Phase I Actionable In a Phase I clinical trial, Kisqali (ribociclib) demonstrated safety and preliminary efficacy in patients with RB1-positive solid tumors and lymphomas, resulting in partial responses in 2.3% (3/132) of patients and stable disease in 32.6% (41/132) of patients, including 8 patients demonstrating stable disease for greater than 6 months (PMID: 27542767, PMID: 24795392). detail... 24795392 27542767