Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer science	110	4	2019 Apr	1420-1430	Cancer Sci

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
Dalpiciclib	Dalpiciclib	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Dalpiciclib		SHR 6390\|SHR-6390\|SHR6390	CDK4/6 Inhibitor 14	Dalpiciclib (SHR6390) 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	Dalpiciclib	Preclinical - Cell culture	Actionable	In a preclinical study, Dalpiciclib (SHR6390) demonstrated little cytotoxic activity against a RB1-negative breast cancer cell line in culture (PMID: 30724426).	30724426
RB1 positive	colon cancer	sensitive	Dalpiciclib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Dalpiciclib (SHR6390) 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	Dalpiciclib	Preclinical - Cell culture	Actionable	In a preclinical study, Dalpiciclib (SHR6390) 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	Dalpiciclib	Preclinical - Cell culture	Actionable	In a preclinical study, Dalpiciclib (SHR6390) demonstrated limited cytotoxic activity against tumor cell lines with low Rb1 expression in culture (PMID: 30724426).	30724426