Study finds unexpected process for the acquisition of drug resistance in cancers of the breast

Study finds unexpected process for the acquisition of drug resistance in cancers of the breast -

A laboratory study revealed a totally unexpected process for the acquisition of drug resistance that bypasses the need to restore DNA damage repair in breast cancer who have BRCA1 or BRCA2 mutants. The results, reported by André Nussenzweig, Ph.D., and Shyam Sharan, Ph.D., at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues, appeared July 21 , 2016, in Nature .

In normal cells, BRCA1 and BRCA2 proteins act as DNA damage sensors, surveyors, and stakeholders. They help to perform complex functions that facilitate the repair of damaged DNA. People who inherit certain mutations in either the BRCA1 or BRCA2 gene have defective DNA repair and increased risk of breast cancer developing, ovarian and other cancers. In particular, mutations in the BRCA1 and BRCA2 genes account for 20 percent to 25 percent of hereditary breast and 5 percent to 10 percent of all breast cancers. The decrease in the ability to repair breaks in DNA in cells with a BRCA1 or BRCA2 mutation renders the cells sensitive to DNA damaging drugs. However, breast cancer eventually develop resistance to these drugs. A documented mechanism for the development of drug resistance in these tumors is by restoring specify the DNA repair pathways that repair DNA breaks caused by chemotherapy.

The Nussenzweig lab has spent the last decade trying to understand the cellular mechanisms that regulate DNA repair in normal and disease states. "These are complex mechanisms that tumor cells evolve to circumvent the need for repair of specific DNA that form the basis of our study," said Nussenzweig. "A deeper understanding of the processes that lead to drug resistance in BRCA1 / 2-mutated tumors will lead to new therapeutic approaches that target specific vulnerabilities of the tumor."

In this study, researchers linked to the protection and stabilization of DNA replication forks as a major contributory mechanism for drug resistance in breast and ovarian / 2 -mutants BRCA1. Replication is a cellular process that produces two DNA copies indistinguishable from a single DNA molecule. This DNA-copying process is an essential step in cell division and occurs at defined locations called replication forks.

The movement of a replication fork as it migrates along a DNA molecule can be disturbed by the presence of a diverse group of DNA structures and proteins, collectively and loosely called replication barriers fork. This disruption results fork Replication migration in what is called a fork stalled. When replication fork stalling, the BRCA1 and BRCA2 proteins are called to protect the newly synthesized DNA strands. If these proteins are absent, the replication fork is destabilized and the newly synthesized DNA is degraded, which increases genomic instability and increases susceptibility to DNA damaging drugs.

The investigators were able to identify other proteins, such as PICTs, CHD4 and PARP1, actively promote the replication fork destabilization by recruiting enzymes that degrade the newly synthesized DNA. The absence of these proteins protected the DNA at replication forks and remarkably reversed the drug sensitivity of both BRCA1 and BRCA2 mutant cells, which makes the drug resistance. These studies also highlighted the complex ways in which tumor cells can escape chemotherapeutic interventions and develop resistance to drugs because disrupting the activity of several proteins directed to the same point of the protection of replication forks the end. These findings are particularly relevant in the clinical setting, where the expression of these proteins appears to be an indicator of how patients with BRCA1 and BRCA2-mutant cancers respond to chemotherapy treatment with DNA damaging agents.

Together, these results highlight the importance of the obstacles replication fork to genomic instability and sensitivity to medication in the context of BRCA1 / 2 The results also suggest that cellular levels these proteins could be used as a prognostic factor of acquired resistance in cancers / 2 BRCA1-mutant.

"Our work starts not only narrow, but also redefine the current dogma in the field, which stipulates that the restoration of DNA repair pathways are the only means by which BRCA1 / 2 mutant cells can become drug resistance, "said Nussenzweig.