Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Abstract

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene. Consequently, BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly (ADP-ribose) polymerase inhibitors (PARPi). Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations, which restore the open-reading frame of the affected allele. This platinum/PARPi cross-resistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies. There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance; however, their actual clinical relevance remains to be established. In addition, studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells. These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure, but become outcompeted by BRCA1-deficient cells during therapy holidays. Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches, which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

Keywords: BRCA1/2 mutations, Platinum-based therapy, Poly (ADP-ribose) polymerase inhibitors, Drug resistance, Secondary mutations, Intratumoral heterogeneity, Neoadjuvant therapy

Core Tip: BRCA1/2-associated tumors are highly sensitive to platinum compounds and poly (ADP-ribose) polymerase inhibitors; however, they eventually acquire resistance to this type of therapy. Restoration of BRCA1/2 function via the second mutation is the most known mechanism of tumor adaptation to the therapeutic pressure. Some studies demonstrate that even chemonaive BRCA1-driven tumors contain a small fraction of BRCA1-proficient cells suggesting that the loss of the remaining allele of this gene is not the first event in tumor pathogenesis. These pre-existing platinum-resistant cells rapidly repopulate tumor mass during neoadjuvant therapy for ovarian cancer and explain inevitability of the disease relapses after seemingly successful surgical debulking.