Inhibiting c-Met could increase potency of PARP inhibitors

Combining PARP inhibitors with inhibitors of the oncogene c-MET could enhance the efficacy of breast cancer treatment, according to a preclinical study published yesterday in Nature Medicine.

The investigation, carried out by researchers at The University of Texas MD Anderson Cancer Center (TX, USA), involved both in vitro and mouse model studies. The team suggest that the findings could hold potential for improving treatment of breast cancer and other malignancies.

Commenting on their findings, lead investigator Mien-Chie Hung (MD Anderson Cancer Center) said: “These findings may predict tumor resistance to PARP inhibitors and suggest that treatment with a combination of c-MET and PARP inhibitors may benefit patients bearing tumors with high c-MET expression who do not respond to PARP inhibition alone.”

The US FDA recently approved the use of the PARP inhibitor olaparib for the treatment of BRCA-mutated breast cancer.

“BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition,” continued Hung. “Combining c-MET and PARP1 inhibitors synergized to suppress growth of breast cancer cells. Similar synergistic effects were also observed in a lung cancer mouse model.”

Hung and colleagues determined that c-MET is responsible for the phosphorylation of PARP1, thus increasing its enzymatic activity and rendering cells resistant to PARP inhibitors. The addition of an an inhibitor of c-MET prevented this phosphorylation, making cells more sensitive to PARP therapy.

“Our study findings raise the interesting possibility that cancer patients with tumors that overexpress c-MET may benefit from this combination therapy regardless of cancer type,” concluded Hung.

Source: The University of Texas MD Anderson Cancer Center press release