Abstract Background: Pleural mesothelioma (PM) remains a highly lethal malignancy with limited therapeutic options. Chemotherapy with cisplatin (CDDP) and pemetrexed provides modest benefit which is limited by primary resistance mechanisms involving dysregulated apoptotic signaling. Myeloid Cell Leukemia (MCL)-1 is a Bcl-2 family member that blocks apoptosis by targeting the mitochondria which works synergistically with activation of autophagy to promote chemoresistance. Targeting MCL-1 lowers the apoptotic threshold and may suppress autophagy to enhance chemosensitivity and improve therapeutic response. This study aimed to determine whether combining MCL-1 inhibition with the antidepressant, desmethyl-clomipramine (DCMI), will enhance chemosensitivity via autophagy in PM cells. Methods: IC50 calculations of CDDP, the MCL-1 inhibitor (AZD-5991), DCMI and the combinations were performed in PM cell lines H28 and H2452. Synergistic interactions were quantified using the Highest Single Agent (HSA) model. To explore autophagy, cells were treated with the autophagy inhibitor, chloroquine (CQ, 10 µM), as a positive control and analyzed for known markers, LC3 and p62, by Western blot. In addition, MCL-1 expression after DCMI combination treatments was evaluated. Cell death and apoptosis were evaluated by flow cytometry (Anexin V and PI) following treatment. Mitochondrial and glycolytic metabolic parameters were quantified by Seahorse XF. Results: CDDP + AZD-5991 exhibited robust synergy (HSA = 10.51, p 0.0001 in H2452; HSA = 9.06, p 0.0001 in H28). In contrast, CDDP and DCMI produced limited interaction in H2452 cells (HSA = 2.48, p = 0.0015) and a near-additive effect in H28 cells (HSA = 0.76, p = 0.175). However, the combination of CDDP, AZD-5991, and DCMI revealed synergistic activity at lower AZD-5991 concentrations, suggesting enhanced potency. DCMI promoted accumulation of p62 and delayed LC3-II processing, consistent with inhibition of autophagy. Furthermore, DCMI + AZD-5991 increased apoptotic cells relative to CDDP alone. These findings suggest enhancement of apoptotic signaling via combined inhibition of autophagy and MCL-1 activity. Seahorse analysis revealed that DCMI decreased basal respiration in H2452, with no effect on H28 bioenergetics. MCL-1 decreases under CDDP + DCMI versus CDDP alone, indicating that DCMI enhances apoptotic priming via MCL-1 suppression and mitochondrial dysfunction. Conclusion: These findings support that complementary mechanisms of DCMI blocking autophagy and MCL-1 promoted apoptosis will enhance the response to cisplatin. This cooperative mechanism reveals metabolic and anti-apoptotic vulnerabilities that could be exploited to overcome chemoresistance in mesothelioma. Further investigation is warranted to assess whether blocking autophagy will increase patient’s response to chemotherapy. Citation Format: Francisco A. Molina-Pelayo, Cristian G. Medina, Jaylon C. Aggison, Naren Li, Siqi Wu, Hainin Yang, Michele Carbone, Yuan Xu, Robert T. Ripley. Mcl-1 inhibitors and antidepressants as enhancers of chemotherapy response in pleural mesothelioma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4660.
Molina-Pelayo et al. (Fri,) studied this question.