Abstract 3491: Rational combination of targeted agents and BH3 mimetics to improve cancer treatment

Abstract

Abstract Background: In the clinic is often observed that melanoma cancer patients first respond to targeted therapeutic agents like dabrafenib showing tumor burden shrinkage, but subsequently relapse with tumors that are more aggressive, no longer responsive to therapy and showing acquired metastatic capacity. Most chemotherapeutic agents kill via the mitochondrial pathway of apoptosis, but unfortunately tumors frequently are able to survive, often adapting their antiapoptotic strategy. We used a variant of the functional predictive test dynamic BH3 profiling (DBP) to determine the tumor's antiapoptotic defense adaptation over time, and rationally identify combination of therapies to restore programmed cell death. Hypothesis: By using different BH3 peptides in DBP we can determine the adaptive tumor's antiapoptotic defense and adjust therapy to improve cancer cell death. Results: In BRAF mutant melanoma, cKIT mutant GIST and HER2 overexpressing breast cancer cell lines, we performed DBP over time using different BH3 peptides: BIM, BAD, PUMA, MS1 and NOXA. We observed that when they are treated with specific targeted agents against their oncogenic drivers, there is an increase in MCL-1 dependence over time. This observation points to a possible tumor defense mechanism conferring resistance against anticancer drugs. Based on these observations, we exploited these altered dependencies by pretreating the cancer cells with these targeted agents and combining them with novel BH3 mimetics targeting MCL-1 to synergistically enhance cell death. Exploiting DBP's capacity to measure changes in priming without the requirement for prolonged ex vivo culture, we assessed if this antiapoptotic evolution was also present in primary melanoma samples. Using FACS-based DBP to select for specific tumor populations, we tested the possible use of BH3 mimetics in combination with targeted agents to improve cancer treatment in the clinic. Conclusions: Our preliminary results reveal the use of dynamic BH3 profiling to be used not only as a powerful real-time tool to predict chemotherapy response but also to evaluate the rational combination of targeted agents with BH3 mimetics in vitro and in the clinic. [R.H. and A.L. contributed equally to this work.] Citation Format: Joan Montero, Dorota E. Sadowicz, Jeremy Ryan, Charles H. Yoon, Rizwan Haq, Anthony Letai. Rational combination of targeted agents and BH3 mimetics to improve cancer treatment. [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 3491.