Overcoming PARP inhibitor resistance, "old" antibiotics show "new" anticancer potential

Cancer is closely related to genetic mutations. The BRCA gene is an important factor involved in DNA repair, and mutations have been found in a significant proportion of breast, ovarian, prostate and pancreatic cancers. The BRCA1 and BRCA2 genes encode proteins that repair DNA damage, and when either of these genes is mutated, cells are unable to repair DNA damage properly, increasing the risk of cancer.

In a new study published today in Nature Cancer, researchers have found that an antibiotic known in the 1950s, novobiocin (NVB), is effective in killing tumor cells that carry homologous recombinant (HR) DNA repair defects. This ability to kill is also effective against tumor cells that have acquired resistance to the poly (ADP) ribose polymerase (PARP) inhibitor. Based on the results, the researchers will launch a clinical trial to test the effects of neonomycin in patients with BRCA-deficient cancer who have developed resistance to PARP inhibitors.

In a study published in 2015, a team of researchers led by Alan D 'Andrea, PhD, one of the paper's corresponding authors, showed that tumors carrying the defective BRCA1 and BRCA2 genes are extremely dependent on a DNA polymerase called polθ, or POLQ, for growth and survival.

In this study, the researchers conducted high-throughput small molecule screening for BRCA-deficient tumors to look for compounds that could affect tumor growth. Among the molecules and drugs being tested, researchers were surprised to find a drug that could kill tumor cells without harming normal ones: neomycin.

The binding target of neothromycin was found to bind to the ATPase domain of POLθ and inhibit its activity, achieving the same inhibitory effect as the knockout of POLθ. Further studies showed that tumor cells carrying homologous recombinant DNA repair defects remained sensitive to neothromycin after acquiring resistance to PARP inhibitors. In these cells, the high level of POLθ expression predicted their sensitivity to neothromycin.

"PARP inhibitors have made important advances in the treatment of cancers that carry BRCA1, BRCA2 or other genetic defects involved in DNA repair. By allowing tumor cells to accumulate additional genetic damage, they cause cell death." "They work for many patients, but cancer cells eventually develop resistance and start growing again, so there is an urgent clinical need for drugs that can overcome this resistance," said Dr Alan D 'Andrea.

The researchers plan to launch a clinical trial to test the efficacy of neonomycin in patients with BRCA-deficient cancer who have developed resistance to PARP inhibitors. Because neomycin is an oral drug that has already been approved for other diseases and has shown good safety, it can be tested more quickly in clinical trials.

References:
[1] Zhou, J., et, al. (2021). A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nature Cancer. Published. https://doi.org/10.1038/s43018-021-00203-x
[2] Antibiotic Novobiocin found to kill tumor cells with DNA-repair glitch. Retrieved June 17, 2021, from https://www.eurekalert.org/pub_releases/2021-06/dci-anf061521.php