Targeting SERPINB5 and MSLN for Pancreatic Cancer Therapy

Abstract

Simple Summary Pancreatic cancer (PC) is a leading cause of cancer-related death, with no effective therapy for curing late-stage PC. Developing effective therapeutic strategies is an emergent unmet need. SERPINB5 is non-inhibitory toward serine proteases, and mesothelin (MSLN) is a tumor-associated antigen. SERPINB5 and MSLN are highly expressed and negatively associated with the overall survival of PC patients. This study shows that SERPINB5 depletion upregulates the mitochondrial protein DHRS2, inducing apoptosis in PC cells. Meanwhile, SERPINB5 depletion increases MSLN transcription, which in turn suppresses DHRS2 and leads to apoptosis resistance. Thus, depleting SERPINB5 and MSLN synergistically induces apoptosis in PC cells. This study shows that SERPINB5-high PC cells are more sensitive to gemcitabine. An in vitro study shows that sequential treatment with gemcitabine followed by anti-MSLN chimeric antigen receptor (CAR)-T cells effectively suppressed PC cell viability, supporting the idea that this combination is a promising therapeutic strategy for PC patients.