Abstract 1657: The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents

Abstract

Abstract DNA damaging agents, such as cisplatin and etoposide, are employed for the treatment of a wide array of solid tumors, but the prolonged use of chemotherapeutic drugs is limited by their toxicity and by the development of resistance. To overcome these major roadblocks to improved prognosis requires mechanism-based therapeutic strategies that maximize the antitumor effect of drugs while limiting their toxicities. These agents exert anticancer effects via multiple mechanisms, yet its most prominent mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of BCL-2 family-dependent mitochondrial apoptosis. Direct therapeutic targeting of the BCL-2 family in cancer is therefore conceptually appealing but has proved remarkably challenging. This is due, in part, to the difficulty in producing effective drugs and in achieving a satisfactory therapeutic index. Also important, but less appreciated in this regard, are the potentially complex, tissue-specific interactions among the BCL-2 family members observed in different tumor types. We have found that the expression of pro-apoptotic Noxa and anti-apoptotic MCL-1 proteins of the BCL-2 family is a critical determinant of the sensitivity to DNA-damaging agents in solid tumors; (1) MCL-1 is a labile protein and its stability is regulated by phosphorylation followed by ubiquitination and proteasome-mediated degradation; (2) Noxa specifically binds to and recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation; (3) The Noxa-dependent phosphorylation sites are regulated by CDK2 and are different from those phosphorylated by CDK1 in response to paclitaxel treatment; (4) Noxa is transcriptionally induced by cisplatin or etoposide. Downregulation of Noxa by shRNA strongly inhibits cisplatin-induced apoptosis. These results suggest that the Noxa/MCL-1 axis plays a critical role in apoptosis induced by DNA damaging agents and targeting Noxa/MCL-1 could be an alternative strategy to overcome the resistance to these agents. Citation Format: Wataru Nakajima, Kanika Sharma, Mark A. Hicks, June Y. Lee, Nobuyuki Tanaka, Hisashi Harada. The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1657. doi:10.1158/1538-7445.AM2015-1657