The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma

// Bo Mi Ku 1, * , Seong Yoon Yi 3, * , Jiae Koh 1 , Yeon-Hee Bae 1 , Jong-Mu Sun 2 , Se-hoon Lee 2 , Jin Seok Ahn 2 , Keunchil Park 2 , Myung-Ju Ahn 2 1 Samsung Biomedical Research Institute, Seoul, Korea 2 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Division of Hematology-Oncology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-do, Korea * These authors contributed equally to this work Correspondence to: Myung-Ju Ahn, e-mail: silk.ahn@samsung.com Keywords: head and neck cancer, CDK4/6 inhibitor, mTOR, cell cycle, targeted therapy Received: September 15, 2015 Accepted: January 23, 2016 Published: February 21, 2016 ABSTRACT Deletion of CDKN2A (p16) or amplification of CCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo . Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo . Taken together, our findings suggest that a combinational treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.