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.

Integrative Genomic Tests in Clinical Oncology

“…Functional tests have an obvious advantage, as they evaluate the genuine activity of HR and can be applied to both chemonaive and pretreated tumors. Indeed, HR proficiency is often rescued during therapy courses through the second mutation restoring the open reading frame of BRCA1/2 or similar genes or by other bypass mechanisms [ 70 ]. The genomic scars described above remain predictive for HRD during the treatment course, even when the actual sensitivity to PARPi or platinum compounds is lost [ 50 ].…”

Opportunities for antitumor drugs replacement

“…Эти клетки, в отличие от нормальных, не способны репарировать двунитевые разрывы ДНК, поэтому они достаточно быстро накапливают критическую массу мутаций в онкогенах и супрессорных генах и подвергаются злокачественной трансформации. В то же время BRCA1/2-ассоциированные опухоли демонстрируют исключительную чувствительность к целому ряду терапевтических агентов [9].…”

“…В целом, BRCA1/2ассоциированные опухоли действительно демонстрируют очень высокую чувствительность к достаточно широкому спектру цитостатических препаратов, что подтверждается результатами многочисленных клинических наблюдений [11]. Примечательно, что адаптация опухолевых клеток к воздействию как PARP-ингибиторов, так и BRCA1/2-специфических цитостатиков, происходит по идентичному механизму, подразумевающему восстановление функции BRCA1/2 [9]. Именно поэтому в случае лечения рака яичников PARP-ингибиторы назначаются только для платиночувствительных разновидностей данного заболевания, а пациентки, у которых возникла резистентность к данному классу лекарственных препаратов, демонстрируют отсутствие эффекта от последующей химиотерапии [14].…”

Cytotoxic and targeted therapy for BRCA1/2-driven cancers

“…Studies on BRCA1 -mutated ovarian carcinomas demonstrated the persistence of a small fraction of BRCA1-proficient cells even in chemonaive tumors; these cells rapidly repopulate tumor mass during the first weeks of platinum-based therapy thus explaining the phenomenon of inevitable emergence of platinum-resistance [ 78 , 79 ]. Therefore, it is potentially error-prone to evaluate the efficacy of BRCA1/2 -specific therapies in the pretreated patients, as the tumors rapidly lose their target and, therefore, adapt to the pressure of platinum compounds or PARPi [ 80 – 82 ].…”