PARP inhibitor resistance and TP53 mutations in patients treated with olaparib for BRCA-mutated cancer: Four case reports

摘要

Loss-of-function BRCA mutations are frequent in high-grade serous ovarian carcinoma. BRCA1 and -2 mutations lead to homologous recombination (HR) deficiency. Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA repair. PARP inhibitors (PARPi) lead to DNA damage accumulation in cells deficient in HR. Olaparib (a PARPi) is currently used for the treatment of high-grade serous ovarian carcinoma with germline or somatic BRCA mutations; however, numerous patients do not respond or eventually develop resistance to these agents. The TP53 gene encodes the p53 protein, which is often referred to as the 'guardian of the genome'. TP53 mutations at diagnosis are known to promote resistance to chemotherapy. In the present study, four cases of patients with BRCA-mutated cancer treated with olaparib, who progressed following the PARPi treatment, are reported. Exome analyses were performed on a primary tumor biopsy at diagnosis, then on a progressing metastasis following olaparib treatment. Exome analyses following olaparib treatment identified de novo TP53 mutations, as well as increased frequencies of pre-existing TP53 mutations compared with the primary tumor. In HCT116 TP53(-/-) cells carrying BRCA2 pathogenic mutations, TP53 inactivating mutations were associated with lower sensitivity to olaparib in vitro. Thus, inactivating TP53 mutations may be associated to olaparib resistance in the presence of BRCA mutations. In conclusion, the present findings demonstrated resistance to PARPi with de novo TP53 mutations that may be clinically relevant. As TP53 mutations are easily detectable with targeted next-generation sequencing panels, these may serve as surrogate markers for the onset of PARPi resistance in the context of routine patient management strategies.