An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

Fagui Chen; Huasi Zhao; Chenhui Li; Ping Li; Qichuan Zhang

doi:10.1038/s41420-022-01082-6

An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

Cell Death Discov. 2022 Jun 18;8(1):293. doi: 10.1038/s41420-022-01082-6.

Authors

Fagui Chen^#¹, Huasi Zhao^#², Chenhui Li³, Ping Li⁴, Qichuan Zhang⁵

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Shantou Central Hospital, Shantou, Guangdong, China.
² Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
³ Department of Pulmonary and Critical Care Medicine, Shenzhen People's Hospital, Shenzhen, Guangdong, China.
⁴ Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China. [email protected].
⁵ Department of Pulmonary and Critical Care Medicine, Shantou Central Hospital, Shantou, Guangdong, China. [email protected].

^# Contributed equally.

Abstract

Molecularly-targeted agents are still urgently needed for better non-small cell lung cancer (NSCLC) therapy. CC-115 is a potent DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) dual blocker. We evaluated its activity in different human NSCLC cells. In various primary human NSCLC cells and A549 cells, CC-115 potently inhibited viability, cell proliferation, cell cycle progression, and hindered cell migration/invasion. Apoptosis was provoked in CC-115-stimulated NSCLC cells. The dual inhibitor, however, was unable to induce significant cytotoxic and pro-apoptotic activity in the lung epithelial cells. In primary NSCLC cells, CC-115 blocked activation of mTORC1/2 and DNA-PK. Yet, CC-115-induced primary NSCLC cell death was more potent than combined inhibition of DNA-PK plus mTOR. Further studies found that CC-115 provoked robust oxidative injury in primary NSCLC cells, which appeared independent of mTOR-DNA-PK dual blockage. In vivo studies showed that CC-115 oral administration in nude mice remarkably suppressed primary NSCLC cell xenograft growth. In CC-115-treated NSCLC xenograft tissues, mTOR-DNA-PK dual inhibition and oxidative injury were detected. Together, CC-115 potently inhibits NSCLC cell growth.