Oncotarget

Research Papers:

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

Bo Mi Ku, Seong Yoon Yi, Jiae Koh, Yeon-Hee Bae, Jong-Mu Sun, Se-hoon Lee, Jin Seok Ahn, Keunchil Park and Myung-Ju Ahn _

PDF  |  HTML  |  How to cite

Oncotarget. 2016; 7:14803-14813. https://doi.org/10.18632/oncotarget.7543

Metrics: PDF 2478 views  |   HTML 3550 views  |   ?  


Abstract

Bo Mi Ku1,*, Seong Yoon Yi3,*, Jiae Koh1, Yeon-Hee Bae1, Jong-Mu Sun2, Se-hoon Lee2, Jin Seok Ahn2, Keunchil Park2, Myung-Ju Ahn2

1Samsung Biomedical Research Institute, Seoul, Korea

2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

3Division 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: [email protected]

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 7543