Abstract
Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of metastatic breast cancer with poor clinical prognosis. Presently used neoadjuvant chemotherapy against TNBC, such as taxanes, and/or anthracyclines show an initial treatment response but follows with drug resistance, tumor relapse, side effects and high proclivity to develop metastases. Recent studies point out that targeting dysregulated mitochondrial dynamics, that is now linked to the tumor initiation, progression, and metastasis in TNBC, as an effective therapeutic strategy. In particular, mitochondrial fission factors such as dynamin-related protein 1 (Drp1) is upregulated in TNBC and is known to affect mitochondrial energetics and alter metabolism which favors tumor progression. We have designed and developed small molecule inhibitors to specifically target Drp1 as a viable therapeutic strategy for metastatic TNBC (mTNBC). We recently identified a new class of structurally constrained thienopyridine (TPH) probes, and particularly a new analog TPH104c that showed higher binding affinity in silico to Drp1 as compared to Mdivi-1, a weak inhibitor of Drp1. Surface plasmon resonance studies suggest that TPH104c binds with Drp1 with high affinity. Similarly, mechanistic studies using Western blotting and immunofluorescence analysis confirmed that TPH104c significantly downregulated the levels of total and phosphorylated form of Drp1 at serine 616 in MDAMB-231 and BT-20 TNBC cells. Interestingly, Drp1 inhibition by TPH104c led to a hitherto unreported form of caspase- and reactive oxygen species (ROS)-independent non-apoptotic form of cell death. Rather than shrinking in size, or formation of apoptotic blebs which are classical features of apoptosis, TPH104c treated TNBC cells were enlarged, rounded, and swollen in size. These cells eventually lost their proliferative ability and were significantly less confluent than control cells. Additionally, in TPH104c-treated cells, neither the mitochondrial membrane potential was lost, nor the caspases were activated as also indicated by a lack of rescue of cell death when incubated with pan-caspase inhibitor. Further studies are in progress to understand the role of Drp1 inhibition in the induction of non-apoptotic cell death which will further help to optimize an effective lead compound for the future pre-clinical development of promising anticancer agents targeting mTNBC. Citation Format: Saloni Malla, Shikha Kumari, David Terrero, Dayanidhi Raman, Amit K. Tiwari. Development of mitochondrial fission inhibitors in inducing non-apoptotic cell death in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3011.
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