Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers diagnosed in the US and causes a fatality rate of more than 90%. Over the past 25 years, progress has been made in limited stage SCLC, where the combination of concurrent radiation and chemotherapy has resulted in a long term survival rate of 20-25%. However, progress has been slow in extensive SCLC (70% of all cases), with long term survival rates of approximately 3% when treated with a variety of multi-agent chemotherapy regimens.
Tumor cell death induced by chemotherapy or lack of appropriate cellular survival signals is mediated by the intrinsic apoptotic pathway. We and others have demonstrated that the anti-apoptotic member BCL-2, as well as BCL-XL and MCL-1, is overexpressed in SCLC. However, until recently, the precise role of these proteins in SCLC biology and therapeutic resistance was poorly understood. The breakthrough came with the development of BH3 mimetic antagonists that block the function of pro-survival BCL-2 family members. ABT-737, the prototype of this new drug class, binds to and blocks BCL-2 and BCL-XL, but not MCL-1 function. Surprisingly, the sensitivity to ABT-737 varies in a broad range in SCLC cells. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is the critical determinant of ABT-737 sensitivity. We show here that Noxa regulates the localization and stability of MCL-1, an anti-apoptotic member, which results in modulating ABT-737 sensitivity. Mutations in Noxa within either the BH3 domain, the carboxyl terminus mitochondrial targeting domain, or of ubiquitinated lysines not only change the localization and stability of Noxa itself, but also affect the mitochondrial localization and phosphorylation/ubiquitination status of MCL-1 and consequently modulate sensitivity to ABT-737. Results of studies utilizing these mutant proteins indicate that Noxa recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation. The precise regulatory mechanisms of Noxa/MCL-1 expression and stability could provide alternative targets to modulate apoptosis induced by BH3 mimetic drugs or other chemotherapeutic reagents.
Citation Format: Wataru Nakajima, Mark A. Hicks, Nobuyuki Tanaka, Geoffrey W. Krystal, Hisashi Harada. Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A23.