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 G 1 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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Trastuzumab‐emtansine (T‐DM1) is an antibody‐drug conjugate that has been approved for the treatment of human epidermal growth factor receptor 2 (HER2)‐positive metastatic breast cancer. Despite the remarkable efficacy of T‐DM1 in many patients, resistance to this therapeutic has emerged as a significant clinical problem. In the current study, we used BT‐474/KR cells, a T‐DM1‐resistant cell line established from HER2‐positive BT‐474 breast cancer cells, as a model to investigate mechanisms of T‐DM1 resistance and explore effective therapeutic regimens. We show here for the first time that activation of signal transducer and activator of transcription 3 (STAT3) mediated by leukemia inhibitory factor receptor (LIFR) overexpression confers resistance to T‐DM1. Moreover, secreted factors induced by activated STAT3 in resistant cells limit the responsiveness of cells that were originally sensitive to T‐DM1. Importantly, STAT3 inhibition sensitizes resistant cells to T‐DM1, both in vitro and in vivo, suggesting that the combination T‐DM1 with STAT3‐targeted therapy is a potential treatment for T‐DM1‐refractory patients.