BRCA-FA pathway as a target for anti-tumor drugs

Abstract

Promising research on DNA repair signaling pathways predicts a new age of anti-tumor drugs. This research was initiated through the discovery and characterization of proteins that functioned together in signaling pathways to sense, respond, and repair DNA damage. It was realized that tumor cells often lacked distinct DNA repair pathways, but simultaneously relied heavily on compensating pathways. More recently, researchers have begun to manipulate these compensating pathways to reign in and kill tumor cells. In a striking example it was shown that tumors derived from mutations in the DNA repair genes, of BRCA-FA pathway, were selectively sensitive to inhibition of the base excision repair pathway. These findings suggest that tumors derived from defects in DNA repair genes will be easier to treat clinically, providing a streamlined and targeted therapy that spares healthy cells. In the future, identifying patients with susceptible tumors and discovering additional DNA repair targets amenable to anti-tumor drugs will have a major impact on the course of cancer treatment.

Figure 1. Schematic representation of the BRCA-FA pathway

Activation of the pathway is required to mediate the DNA damage response, repair, and checkpoint response to maintain genomic stability. Loss or inactivation of this pathway leads to defects in DNA repair and/or checkpoint responses that reduce cell survival following ICL-treatment.

Figure 2. Exploiting defects in BRCA-FA cancers as a therapeutic strategy

The viability of healthy cells is maintained by repair being processed by multiple DNA damage repair pathways, represented as four legs of a table. However, tumor cells that lack a distinct DNA repair pathway(s), will rely more heavily on other compensating pathway(s) for survival. Disrupting these compensating DNA repair pathways may selectively compromise tumor cell survival (table falls over), while maintaining the viability of healthy cells (table remains standing on three legs). Here, we discuss the possibility that loss or inactivation of the BRCA-FA pathway is an ideal target for this type of targeted approach.