Study Explores How Breast Cancers Resist Chemotherapy
A laboratory study led by scientists at the National Institutes of Health investigating how BRCA1- and BRCA2-mutant cell breast cancers eventually acquire resistance to DNA-damaging drugs has identified several proteins that promote destabilization of replication forks and contribute to drug resistance (including PTIP, CHD4, and PARP1). The results of these findings, reported by Chaudhuri et al in Nature, suggest that the cellular levels of these proteins might be used as a prognostic factor in acquired resistance to BRCA1/2-mutant cancers.
Chemoresistance
According to the investigators, the role of BRCA1 and BRCA2 in the repair of double-strand breaks is believed to be central to their tumor-suppressor activities and makes the BRCA-deficient cells sensitive to DNA-damaging drugs such as cisplatin and PARP (poly [ADP-ribose] polymerase) inhibitors. And although cisplatin and PARP inhibitors have been shown to be effective agents, most BRCA-mutant cancers acquire resistance.
In this study, the researchers linked the protection and stabilization of DNA-replication forks as a major contributing mechanism to drug resistance in BRCA1/2-mutant breast and ovarian cancers.
Study Findings
The researchers identified several proteins that actively promote destabilization of replication forks. These proteins, which include PTIP, CHD4, and PARP1, recruit enzymes that degrade newly synthesized DNA. The absence of these proteins protected the DNA at replications forks and reversed the drug sensitivity of BRCA1- and BRCA2-mutant cells.
To test whether differential levels of PTIP expression could be an indicator of patient response to platinum chemotherapy, the researchers analyzed clinical information from The Cancer Genome Atlas of patients with BRCA1/2-mutated ovarian serous adenocarcinoma treated with platinum chemotherapy. Survival analysis showed that platinum-treated BRCA2 mutants with high PTIP expression were correlated with a longer progression-free survival. Lower expression of PTIP also predicted a shorter progression-free survival in BRCA2-associated ovarian cancers.
“These data suggest that PTIP levels could be a biomarker for acquired resistance to platinum-based chemotherapy in BRCA1/2-mutated ovarian cancers,” concluded the study authors.
“It is the intricate mechanisms that tumor cells evolve to bypass the need for accurate DNA repair that form the foundation of our study,” said André Nussenzweig, PhD, Senior Investigator in the Laboratory of Genome Integrity at the National Institutes of Health, in a statement. “A deeper knowledge of the processes that drive drug resistance in BRCA1/2-mutant tumors will lead to novel therapeutic approaches that target tumor-specific vulnerabilities.”
The study authors declared no competing financial interests.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
