Abstract C6: Antiapoptotic defense evolution in cancer: novel therapeutic strategies to restore cell death using dynamic BH3 profiling

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Abstract Background: There is a lack of effective predictive biomarkers to efficiently assess the optimal treatment for each patient and overcome resistance. When effective death signaling is initiated by a targeted therapy, an increase in mitochondrial apoptotic sensitivity (or ‘priming for death’) can be observed within hours with Dynamic BH3 Profiling (DBP). Most chemotherapeutic agents kill via the mitochondrial pathway of apoptosis, but unfortunately tumors frequently are able to survive adapting their antiapoptotic strategy. By using different BH3 peptides we can determine the tumor's defense adaptation over time and find novel ways to rationally develop combination therapies and restore apoptotic cell death. Hypothesis: Analyzing the tumor's antipoptotic defense over time with DBP we can predict how the tumor will adapt to the first-line therapy and restore cell death using BH3 mimetics. Results: Our first set of experiments consisted in characterizing the tumor's adaptation to therapy over time. We performed DBP over time using different BH3 peptides: BIM, BAD, MS1, PUMA and NOXA. In GIST and melanoma cell lines, we observed that when they were effectively treated with imatinib (KIT inhibitor) and dabrafenib (BRAFV600E inhibitor) respectively, or to selumetinib (MEK inhibitor) in both cases, there was an increased dependence in MCL-1 between 24 and 48 hours. This observation explains a possible mechanism by which tumors adapt their antiapoptotic dependencies. Based on these observations, we exploit these altered dependencies by pretreating the cancer cells with the above mentioned targeted therapies and then add a specific MCL-1 inhibitor to restore cell death. Other cell lines, including breast cancer and melanoma, were subsequently studied, and the combination of specific targeted therapies with BH3 mimetics (ABT-199, ABT-263 and MCL-1 inhibitors) was also assessed. Exploiting DBP's capacity to measure changes in priming without the requirement for prolonged ex vivo culture, we assessed if this antipoptotic evolution was also present in primary melanoma samples. We tested combinations of targeted therapies with BH3 mimetics to incorporate antiapoptotic targets to cancer treatment. Conclusions: Our cell line and clinical experiments demonstrate the potential for Dynamic BH3 profiling to be used as a powerful real-time tool to predict chemotherapy response and evaluate induced dependencies in relapsed patients. By studying combinations of targeted agents with BH3 mimetics we aim to improve cancer treatment. Citation Format: Joan Montero, Dorota E. Sadowicz, Rizwan Haq*, Anthony Letai*. Antiapoptotic defense evolution in cancer: novel therapeutic strategies to restore cell death using dynamic BH3 profiling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C6.