BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors

Abstract

Background We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors. Methods The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models. Results Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively. Conclusion A clinical trial may be justified to further investigate the utility of IAP inhibitors.

Effective Anticancer Potential of a New Sulfonamide as a Carbonic Anhydrase IX Inhibitor Against Aggressive Tumors

“…[89] HTRA and SMAC genes also function as inhibitors of IAP in apoptosis activation. Increased IAP expression has been linked to poor prognosis in esophageal [90,91] and breast [92] cancers. Several studies have suggested that heat shock proteins (HSPs) may shield mitochondrial functions and prevent apoptotic signals in cancer cells.…”

Prognostic value and therapeutic potential of IAP family in head and neck squamous cell carcinoma

“…A growing body of research in recent years has illustrated a link between alterations in IAP expression and the onset and progression of tumours, as well as medication resistance. Researchers have found that BRCA mutations lead to XIAP overexpression, making ovarian cancer sensitive to the IAP family [ 12 ]. BIRC5 stimulates cellular apoptosis, diminishes the growth capacity of tumours, and renders cancerous cells more susceptible to chemotherapeutic agents (e.g., etoposide, Taxol, cisplatin), immunotherapy, and gamma radiation [ 29 ].…”

“…Research has revealed that the IAP family plays a role in cell cycle regulation, cell migration, and other biological processes [ 9 – 11 ]. Aberrant expression of its members is linked to the development of tumours [ 12 – 15 ] and can serve as tumour markers [ 16 , 17 ].…”

Combined inhibition of XIAP and autophagy induces apoptosis and differentiation in acute myeloid leukaemia

“…Mounting evidence demonstrates that XIAP promotes the growth, invasion, and metastasis of malignant cells, confers resistance to certain chemotherapeutic drugs, and associates with poor outcome in a variety of cancers 3,4 . Overexpression of XIAP is frequently observed in human cancers and may contribute to tumorigenesis by evading cancer cell apoptosis 5,6 . As for AML, multiple reports have regarded XIAP as a unfavourable gene through a variety of signal pathways, including caspase pathway 7,8 and NF‐kB pathway, 9 and inhibition of XIAP can sensitize AML cells to tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) 10,11 .…”

“…3,4 Overexpression of XIAP is frequently observed in human cancers and may contribute to tumorigenesis by evading cancer cell apoptosis. 5,6 As for AML, multiple reports have regarded XIAP as a unfavourable gene through a variety of signal pathways, including caspase pathway 7,8 and NF-kB pathway, 9 and inhibition of XIAP can sensitize AML cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). 10,11 Recently, several studies also show that XIAP inhibitors can increase the efficacy of BCL2 inhibitors 12 or affect AML myelomonocytic differentiation.…”