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Review
. 2017 Jun;12(6):565-581.
doi: 10.1080/17460441.2017.1322061. Epub 2017 May 2.

Therapeutic targeting and patient selection for cancers with homologous recombination defects

Francien Talens  1 , Mathilde Jalving  1 , Jourik A Gietema  1 , Marcel A Van Vugt  1
Affiliations
Free article
Review

Therapeutic targeting and patient selection for cancers with homologous recombination defects

Francien Talens et al. Expert Opin Drug Discov. 2017 Jun.
Free article

Abstract

DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected. Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer. In addition, mechanisms of acquired PARP inhibitor resistance are discussed. Furthermore, combination therapies with PARP inhibitors are reviewed, in the context of both HR-deficient and HR-proficient tumors and methods for proper patient selection are also discussed. Expert opinion: Currently, only patients with germline or somatic BRCA1/2 mutations are eligible for PARP inhibitor treatment and only a proportion of patients respond. Patients with HR-deficient tumors caused by other (epi)genetic events may also benefit from PARP inhibitor treatment. Ideally, selection of eligible patients for PARP inhibitor treatment include a functional HR read-out, in which cancer cells are interrogated for their ability to perform HR repair and maintain replication fork stability.

Keywords: BRCA1; BRCA2; Lynparza; PARP inhibitor; genome instability; homologous recombination; olaparib; personalized medicine; synthetic lethality.

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