Abstract 1655: Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines.

Autophagy is a stress-induced cellular reaction in cancer cells. Recent studies showed that cyclin dependent kinase inhibitor proteins, such as p27 or p16, also induced cytoprotective autophagy in cancer cells. However, it is not clear whether small molecule CDK inhibitors also induce autophagy in solid cancer cells. In this study, we revealed that CDK4 inhibitor and a broad-range CDK inhibitor (flavopiridol) induced autophagy in some solid cancer cell lines, but not all. The autophagy induced by CDK4 inhibitors was observed in BT474, MDA-MB435S, SKBr3 (derived from breast cancer), A431 (derived from lung cancer) and SW480 (derived from colorectal cancer), While it was not observed in MCF7, MDA-MB231 (derived from breast cancer), NCI-N87 (derived from gastric cancer) and KMST-6 (derived from fibroblast). In the cell lines which were induced autophagy by CDK inhibitors, the combination of a CDK4 inhibitor and an autophagy inhibition, by either chloroquine or knockdown of ATG5 or BECN1, induced apoptosis. However it did not induce apoptosis in the cell lines which were not induced autophagy by CDK4 inhibitor. From these results, the autophagy induced by CDK4 inhibitor mimic the stress-induced autophagy in some solid cancer cell lines. The combination of a small-molecule CDK inhibitor and an autophagy inhibitor is a synthetic lethal interaction and could become a new antitumor strategy in solid tumors which are induced cytoprotective autophagy by CDK inhibitors. Citation Format: Yoshinari Okada, Shunsuke Kato, Yasuhiro Sakamoto, Takayuki Oishi, Chikashi Ishioka. Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1655. doi:10.1158/1538-7445.AM2013-1655