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

World Journal of Clinical Oncology 2021年第7期12卷 544-556页

作者： Evgeny Imyanitov Anna Sokolenko Department of Tumor Growth Biology N.N.Petrov Institute of OncologySaint-Petersburg 197758Russia Department of Medical Genetics St.-Petersburg Pediatric Medical UniversitySaint-Petersburg 194100Russia Department of Oncology I.I.Mechnikov North-Western Medical UniversitySaint-Petersburg 191015Russia

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 crossresistance 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.

关键词： BRCA1/2 mutations Platinum-based therapy Poly(ADP-ribose)polymerase inhibitors Drug resistance secondary mutations Intratumoral heterogeneity Neoadjuvant therapy

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