Abstract 3555: Targeting the BCL-2 family in small cell lung caner
Authors: Inoue-Yamauchi Akane , Jeng Paul , Kim Kwanghee , Chen Hui-Chen , Han Song , Ganesan Yogesh Tengarai , Dong Yiyu , Jebiwott Sylvia , Hsieh James J. , Cheng Emily H. 
Published: July 2016

Abstract
Small cell lung cancer (SCLC) represents 13% of all lung cancer cases, affecting approximately 30,000 people annually in the United States. The prognosis for patients with SCLC is poor, and cancer-specific mortality of this malignancy is 95% at five years. This dismal prognosis has been further marred by the absence of major improvements in its treatment: there have been no substantial changes in the standard of care for advanced SCLC over the last three decades. Interestingly, small molecule inhibitors of anti-apoptotic BCL-2 family members BCL-2 and BCL-XL, ABT-737 and its orally bioavailable analog ABT-263, were shown to effectively kill some SCLC cell lines in preclinical studies, suggesting that targeting the BCL-2 family proteins may hold promise for the treatment of this dreadful cancer. However, these inhibitors do not inhibit MCL-1, another anti-apoptotic BCL-2 family member, which may explain why multiple clinical trials have not led to meaningful results. Because there are no effective MCL-1 inhibitors developed yet, we propose to identify the best strategy that enhances the apoptotic effect of ABT-737/263. To this end, we have performed a high-throughput screen in ABT-737/263 resistant H196 cell lines using two libraries, a library of FDA-approved anti-cancer agents and a pathway inhibitor library including ∼1000 compounds. As a result, doxorubicin and dinaciclib were identified as synergizers of ABT-737/263 in triggering apoptosis. These two drugs enhanced the death inducing activity of ABT-737/263 through downregulation of MCL-1 mRNA. Interestingly, some of the ABT-737/263 resistant cell lines rely on MCL-1 for survival and thereby were killed by dinaciclib or doxorubicin as a single agent, indicating that predictive biomarkers of cellular addiction to anti-apoptotic BCL-2 family proteins (BCL-2s) can guide treatment decisions and reduce unwanted toxicity. Importantly, we revealed that the expression ratio between BCL-2, BCL-XL, and MCL-1 could predict cellular addiction to BCL-2s. Surprisingly, we demonstrated that BCL-XL overexpression is an another potential mechanism behind ABT-263 resistance. ABT-263 failed to inhibit the interaction between BCL-XL and BAX/BAK in the absence of activator BH3-only molecules and thereby failed to kill one BCL-XL-addicted SCLC cell line with low expression of activator BH3-only molecules. Finally, we showed that BCL-2 selective inhibitor ABT-199 can also cooperate with doxorubicin or dinaciclib to kill ABT-263-resistant cell lines. The in vivo efficacy of combination therapy including ABT-199 and doxorubicin was demonstrated in a SCLC xenograft model. These data have direct translational implications for the treatment of SCLC.
Citation Format: Akane Inoue-Yamauchi, Paul Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Yiyu Dong, Sylvia Jebiwott, James J. Hsieh, Emily H. Cheng. Targeting the BCL-2 family in small cell lung caner. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3555.