Abstract 2496: Dynamic BH3 profiling identifies active combinations with conventional chemotherapy in non-small cell lung cancer
Authors: Potter Danielle S. , Letai Anthony G. 
Published: August 2019

Abstract
Mitochondrial apoptotic priming (referred to as priming) determines a cell’s ‘readiness’ for cell death and is regulated by the B-cell lymphoma 2 (BCL-2) family of proteins. It has been shown in multiple disease settings such as acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma and ovarian cancer, that chemosensitivity correlates with priming. Patients with highly primed tumors exhibited superior clinical response to chemotherapy. In contrast, chemoresistant cancers and normal tissues were poorly primed. Priming is relative and can be measured using BH3 profiling. BH3 profiling is a functional assay which uses BH3 peptides derived from the BH3 domain of pro-apoptotic BH3-only BCL-2 family members to provoke a response from viable mitochondria. To identify drugs that enhance priming, tumor cells can be incubated with drugs prior to BH3 profiling, a method called dynamic BH3 profiling (DBP). DBP is a functional approach to precision medicine and measures early changes in death signaling after drug perturbation. An increase in priming after short term drug treatment (8-24 hours) has been shown to result in cell death days later. Moreover, it has been shown to predict in vivo response to therapy. Therefore, DBP can predict efficacious therapies within 24 hours.We hypothesized that drugs that enhance priming would render cancers more sensitive to conventional chemotherapy. To determine whether drugs that increase priming enhanced sensitivity to docetaxel and etoposide in non-small cell lung cancer (NSCLC), we first identified agents that enhanced priming via DBP. We found that targeted agents that increased priming of NSCLC tumor cells resulted in increased chemosensitivity in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo, we carried out an efficacy study in PC9 xenograft mouse model. The BH3 mimetic navitoclax, which inhibits BCL-xL, BCL-w and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which inhibits BCL-2, did not. In vivo navitoclax reduced tumor burden whilst mice were treated but as soon as therapy was stopped tumors recovered comparable to vehicle treated mice. Etoposide as a single agent had no effect on tumors. However, combining navitoclax with etoposide significantly reduced tumor burden after treatment was stopped, increasing mouse survival. Adding venetoclax to etoposide had no effect on tumor burden. These data suggest that targeted agents that increase priming, increased chemosensitivity resulting in reduction of tumor burden in vivo.
Citation Format: Danielle S. Potter, Anthony G. Letai. Dynamic BH3 profiling identifies active combinations with conventional chemotherapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2496.