Research Shows New Possibilities for PARP Inhibitors in Lung Cancer

Combination therapies with PARP inhibitors have proven to be effective in targeting multiple types of illnesses, including cancer. A new study shows that a PARP inhibitor combined with a DNA methyltransferase (DNMT) inhibitor may be a new way of treating some lung cancers.

Researchers from the University of Maryland School of Medicine (UMSOM) published data from a proof-of-concept study in the journal PNAS that showed combining a PARP inhibitor with a DNMT inhibitor was effective in treating non-small cell lung cancer tumors. The results were surprising, since PARP inhibitors have typically been associated with solid tumors that have BRCA gene mutations. The Maryland research conducted in mice models and cell lines, showed that the DNMT inhibitor triggers an effect that mimics a BRCA mutation in the cancer cell, which causes the positive response from the PARP inhibitor.

DNMT inhibitors suppress DNA methylation, which leads to changes in gene expression that significantly interfere with cancer cell growth. They have been for use in myelodysplastic syndromes, which are cancers of the bone marrow. This study is one of the first, if not the first, to combine DMNT inhibitors with PARP inhibitors.

Researchers have been exploring the possibility that PARP inhibitors can play a greater role in the treatment of cancer beyond those BRCA mutations. A recent study from UT Southwestern demonstrated the potential of PARP inhibitors in other cancers. The study showed that PARP inhibitors can act by a mechanism different from the BRCA-dependent DNA repair pathways. PARP stands for poly ADP ribose polymerase, which is an enzyme many cancer cells are more dependent upon than regular, healthy cells are.

Feyrus V. Rassool, a professor of radiation oncology at the University of Maryland School of Medicine, noted that their study data shows the combination of the PARP and DMNT inhibitors cause interactions that significantly disrupt cancer cells' ability to survive DNA damage. The findings, similar to those of UT Southwestern, can expand the use of PARP inhibitors beyond the minority of inherited cancers that it now treats, Rassool said.

This new study from UMSOM is the first to demonstrate that cells can be induced to resemble the BRCA mutation, a “BRCAness” phenotype or gene expression, that is not the result of a mutation by treating them with the DNA methyltransferase inhibitor drug, the university said in its announcement. When that occurs, the tumor will respond to the PARP inhibitor drugs aimed at the BRCA mutation. The researchers also found that the DNMT and PARP inhibitor combination prevented cancer cells from repairing the DNA damage caused by radiation, a common treatment for lung cancer, the university said.

“We are very excited by the new finding because it explains the mechanistic action of this drug combination, which we found has a synergistic effect, and so works better than either drug alone,” Polly Abbotts, first author of the study and a postdoctoral fellow in the Department of Radiation Oncology said in a statement. “When we combined with radiation therapy, which is the standard treatment for lung cancer, we measured an even bigger effect.”

The researchers are now aiming to test this protocol in an early phase trial in patients with non-small cell lung cancer. Two years ago, Rassool’s research team demonstrated that this novel drug combination worked to disrupt cancer cells in acute myeloid leukemia and they are now testing the protocol in a trial of cancer patients with AML. Early results suggest that this drug combination is well tolerated.