simmiparib (SMOCL-9112) / Shanghai Acebright Pharma - LARVOL DELTA

Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer. (PubMed, Cell Death Dis) - "Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRCA1 • GSK3B • HRD

Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors. (PubMed, Am J Cancer Res) - "In this study, we generated three PARPi-resistant BRCA2-deficient pancreatic Capan-1 variant cells using olaparib (Capan-1/OP), talazoparib (Capan-1/TP), and simmiparib (Capan-1/SP)...Furthermore, exogenous addition of prostaglandin E2, a major metabolic product of COX-2, inhibited PARPi-induced apoptotic signals; however, when combined with the BIRC3 inhibitor LCL161, there was significantly enhanced sensitivity of the resistant variants to PARPi. Finally, PARPi treatment or PARP1 depletion led to a marked increase in the mRNA and protein levels of COX-2 and BIRC3, indicating that PARP1 is a negative transcriptional regulator of these proteins. Together, our findings demonstrated that during the chronic treatment of cells with a PARPi, both BRCA2 intron 11 mutations and COX-2/BIRC3-mediated apoptotic resistance led to PARPi resistance in pancreatic Capan-1 cells."

Journal • Oncology • BIRC3 • BRCA2 • CASP3 • CASP9