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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|SHR6390||SHR 6390|SHR-6390|Dalpiciclib||CDK4/6 Inhibitor 13||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 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|
|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 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 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|