Secondary mutations of BRCA1/2 and drug resistance

Abstract

Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 cause increased risk of developing various cancers, especially breast and ovarian cancers. Tumors that develop in patients with inherited BRCA1/2 mutations are generally believed to be BRCA1/2-deficient. Cancer cells with BRCA1/2 deficiency are defective in DNA repair by homologous recombination and sensitive to interstrand DNA crosslinking agents, such as cisplatin and carboplatin, and poly(ADP-ribose) polymerase inhibitors. Therefore, these agents are logical choices for the treatment for BRCA1/2-deficient tumors and have shown to be clinically effective. However, BRCA1/2-mutated tumors often develop resistance to these drugs. Restoration of BRCA1/2 functions due to secondary BRCA1/2 mutations has been recognized as a mechanism of acquired resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors in BRCA1/2-mutated cancer cells. This indicates that even disease-causing inherited mutations of tumor suppressor genes can be genetically reverted in cancer cells, if the genetic reversion is advantageous for the cells' survival. In this review, we will discuss this drug resistance mechanism.

Fig. 1. Implications of DNA repair defects in cancer

DNA repair defects (for example, defect of homologous recombination due to BRCA1/2 deficiency) can contribute to genomic instability, which promotes malignant transformation of cells. They also lead to cellular sensitivity to certain DNA damaging agents. Restoration of DNA repair (for example, restoration of homologous recombination DNA repair due to functional restoration of BRCA1/2) can lead to acquired resistance to the DNA damaging agents.

Fig. 2. Model for involvement of BRCA1/2 restoration in acquired resistance to platinum chemotherapy

(adapted with modifications from Sakai et al, Nature 2008;451(7182): 1116–20, supplemental material). Initially tumors are BRCA1/2 deficient and sensitive to platinum compounds (cisplatin and carboplatin). Rare cells restore functional BRCA1/2 due to secondary BRCA1/2 mutation. The secondary mutation may occur during the course of chemotherapy or may pre-exist prior to chemotherapy. BRCA1/2 deficiency and treatment with DNA damaging agents can lead to increased mutation rate, which contribute to occurrence of secondary mutations in BRCA1 and BRCA2 themselves. Treatment with platinum compounds can also serve as a selective pressure for BRCA1/2-restored cells. BRCA1/2-restored cells survive the treatment and proliferate to form a BRCA1/2-proficient tumor, which would be resistant to both platinum compounds and PARP inhibitors.