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Ref Type Journal Article
PMID (30724426)
Authors Long F, He Y, Fu H, Li Y, Bao X, Wang Q, Wang Y, Xie C, Lou L
Title Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models.
Journal Cancer science
Vol 110
Issue 4
Date 2019 Apr
URL
Abstract Text Inhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) pathway is an effective therapeutic strategy against cancer. Here, we performed a preclinical investigation of the antitumor activity of SHR6390, a novel CDK4/6 inhibitor. SHR6390 exhibited potent antiproliferative activity against a wide range of human RB-positive tumor cells in vitro, and exclusively induced G1 arrest as well as cellular senescence, with a concomitant reduction in the levels of Ser780-phosphorylated RB protein. Compared with the well-known CDK4/6 inhibitor palbociclib, orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts, and produced marked tumor regression in some models, in association with sustained target inhibition in tumor tissues. Furthermore, SHR6390 overcame resistance to endocrine therapy and HER2-targeting antibody in ER-positive and HER2-positive breast cancer, respectively. Moreover, SHR6390 combined with endocrine therapy exerted remarkable synergistic antitumor activity in ER-positive breast cancer. Taken together, our findings indicate that SHR6390 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties for use as an anticancer agent.

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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
SHR6390 SHR 6390|SHR-6390|Dalpiciclib CDK4/6 Inhibitor 11 SHR6390 (dalpiciclib) inhibits CDK4/6, which may lead to cell cycle arrest and tumor growth inhibition (PMID: 30724426).
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 colon cancer sensitive SHR6390 Preclinical - Cell line xenograft Actionable In a preclinical study, SHR6390 (dalpiciclib) inhibited CDK4/6-RB pathway activation, leading to growth inhibition in an RB1-positive colon cancer cell line in culture, and tumor regression in a cell line xenograft model (PMID: 30724426). 30724426
RB1 positive Advanced Solid Tumor sensitive SHR6390 Preclinical - Cell culture Actionable In a preclinical study, SHR6390 (dalpiciclib) inhibited CDK4/6-RB pathway signaling, leading to cell cycle arrest and inhibition of proliferation in a panel of RB1-positive tumor cell lines in culture, and tumor growth inhibition in cell line xenograft models (PMID: 30724426). 30724426
RB1 dec exp Advanced Solid Tumor no benefit SHR6390 Preclinical - Cell culture Actionable In a preclinical study, SHR6390 (dalpiciclib) demonstrated limited cytotoxic activity against tumor cell lines with low Rb1 expression in culture (PMID: 30724426). 30724426
RB1 negative breast cancer no benefit SHR6390 Preclinical - Cell culture Actionable In a preclinical study, SHR6390 (dalpiciclib) demonstrated little cytotoxic activity against a RB1-negative breast cancer cell line in culture (PMID: 30724426). 30724426