PARP Inhibitors May Enhance Immunotherapy Response in Lung Cancer

A recent study showed poly (ADP-ribose) polymerase (PARP) inhibitors may enhance the immune response against cancer cells, indicating that the therapy could help improve patients’ response to immunotherapy.

Although immunotherapies have led to vast improvements in the treatment of cancer, particularly in non-small cell lung cancer (NSCLC), only a minority of the patients treated experience a long-term benefit. Defects in the DNA damage response (DDR) cancer cells are key determinants in cancer immunogenicity. DDR defects can lead to genomic instability and increased tumor mutational burden, according to the study.

PARP inhibitors, such as olaparib, attack tumors that are defective at DNA repair, especially in ovarian and breast cancers in women with inherited BRCA mutations. The current study assesses PARP inhibitors’ immunomodulatory potential in lung cancer.

The study, published in The Journal of Clinical Investigation, examined lung tumors taken from patients, as well cancer cells from NSCLCs and triple-negative breast cancers with mutations in DNA repair genes, such as ERCC1 and BRCA, to determine whether PARP inhibitors could boost the immune response.

According to the study, lung tumors containing deficiencies in their DNA repair had significantly more immune cells within the tumors compared with tumors in patients with a functioning DNA repair system. In cancer cells with defective repair systems, their remaining system of DNA repair is further blocked by treatment with PARP inhibitors, leading to eventual death.

The researchers found that the accumulation of DNA damage in these treated cancer cells triggered the release of molecular signals that could potentially attract immune cells to the tumor. By drawing the immune cells to the tumor, PARP inhibitors could enable the immunotherapy drug to target their attack and enhance the therapeutic effect.

“The findings of this study substantially change our understanding of how PARP inhibitors work,” study leader Chris Lord, professor of cancer genomics at The Institute of Cancer Research, said in a press release. “We now know that they not only kill tumors by damaging their DNA, but also by attracting immune cells to attack them—acting as a sort of double-pronged attack.”

The study also showed that this response was amplified in ERCC1-deficient cancer cells, which is the most common DDR deficiency in NSCLC. According to the results, in 1 ERCC1-deficient cancer cell line, 24 out of 50 signaling pathways that were activated after treatment with PARP inhibitors were related to the immune system. These findings indicate the potential for PARP inhibitors in combination with immunotherapy to have a more effective impact in treating patients with NSCLC.

Overall, the data suggest the immunomodulatory potential of PARP inhibitors that could be therapeutically exploited to enhance immune checkpoint inhibitor efficacy, particularly in ERCC1-deficient NSCLC, the researchers concluded.

References

Chabanon RM, Muirhead G, Krastev DB, et al. PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer. The Journal of Clinical Investigation. 2018. Doi: 10.1172/JCI123319

Precision drugs could unmask cancers to the immune system and boost the effects of immunotherapy [news release]. The Institute of Cancer Research. https://www.icr.ac.uk/news-archive/precision-drugs-could-unmask-cancers-to-the-immune-system-and-boost-the-effects-of-immunotherapy. Accessed March 11, 2019.