SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Resistance to chemotherapy and PARPi inhibitors remains a critical challenge in the treatment of epithelial ovarian cancer, mainly due to disabled apoptotic responses in tumor cells. Given mesothelin's pivotal role in ovarian cancer and its restricted expression in healthy tissues, we conducted a drug-screening discovery analysis across a range of genetically modified cancer cells to unveil mesothelin's therapeutic impact. We observed enhanced cell death in low mesothelin expressing cancer cells when exposed to a second mitochondria-derived activator of caspases (SMAC) mimetics, and demonstrated a compelling synergy when combined with chemotherapy in ex vivo patient-derived cultures and zebrafish tumor xenografts. Mechanistically, the addition of the SMAC mimetics drug birinapant to either carboplatin or paclitaxel triggered the activation of the Caspase 8-dependent apoptotic program facilitated by TNF alpha signaling. Multimodal analysis of neoadjuvant-treated patient samples further revealed an association between tumor-associated macrophages and the activation of TNF alpha-related pathways. Our proposed bimodal treatment shows promise in enhancing the clinical management of patients by harnessing the potential of SMAC mimetics alongside conventional chemotherapy. ### Competing Interest Statement The authors have declared no competing interest.