Skip to main content
Premium Trial:

Request an Annual Quote

Tumor Cell, Mouse Studies Suggest c-Met Expression as Predictor of PARP Inhibitor Resistance

NEW YORK (GenomeWeb) – New data from in vitro and mouse model studies suggest that combining a PARP inhibitor with a c-Met inhibitor may help cancer patients with high c-Met expression to overcome resistance to PARP inhibition.

The experiments in triple-negative breast cancer cell lines and tumor models, published in Nature Medicine this week, showed that c-Met "associates with and phosphorylates" PARP1, which bolsters PARP1 enzymatic activity. This mechanism may be an explanation for why some cancer patients don't respond to PARP inhibitors, according to researchers led by Mien-Chie Hung from the University of Texas MD Anderson Cancer Center.

Hung's team demonstrated that when c-Met expression was knocked down in TNBC cell lines treated with three different PARP inhibitors — Lynparza (olaparib), veliparib, and rucaparib — it rendered tumor cells more sensitive to treatment and less viable. Moreover, when these cells lines were treated with a c-Met inhibitor — Xalkori (crizotinib) or foretinib — it enhanced their sensitivity to PARP inhibitors.

The DNA damage and repair process is key to normal cell survival. Since PARP1 enzymes play a critical role in repairing single-stranded DNA breaks, drugmakers have theorized that therapies that immobilize this repair pathway could kill cancer cells by hobbling their ability to fix DNA damage, an ability necessary to their survival.

But cancer cells can find other ways to repair DNA damage — with the help of genes such as BRCA1 and BRCA2, for example. As such, research has shown that PARP inhibitors are particularly effective in some cancer patients with mutations in BRCA1/2 that make them DNA-repair deficient.

In 2014, the US Food and Drug Administration approved the first PARP inhibitor, AstraZeneca's Lynparza, for advanced ovarian cancer patients who have germline mutations in BRCA1 and BRCA2 genes. However, as Hung and his colleagues point out in their paper, BRCA mutations have not been consistently predictive of Lynparza benefit in TNBC patients. One study in TNBC patients showed that patients with BRCA mutations benefited from treatment, while another failed to show the same efficacy.

Attempting to shed light on this discrepancy, Hung's team investigated two breast cancer cell lines with BRCA1 mutations, one sensitive to PARP inhibitors and another resistant. Western blot analysis showed that the resistant cell lines had higher c-Met expression. But when researchers knocked down c-Met expression in the resistant cell lines, it rendered the cells more sensitive to PARP inhibition.

To explore this relationship another way, Hung's team knocked down BRCA1 and BRCA2 expression in two cell lines with wild-type versions of these genes, where one of the lines had high c-Met expression and the other had low expression. With BRCA expression knocked down, only the low c-Met expressing cells were sensitive to PARP inhibitors.

Hung's team believe these results suggest that high c-Met expression makes cells resistant to PARP inhibitors, even in the presence of BRCA1 and BRCA2 abnormalities, and offers a potential explanation for why some TNBC patients with BRCA mutations still don't respond to PARP inhibitors.

"BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition," Hung said in a statement. "Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells."

The researchers observed similar effects of the c-Met and PARP inhibitor combination in a mouse model of lung cancer. Based on this, Hung and his team recommended further evaluation of the combination treatment in c-Met overexpressing tumors beyond TNBC.

These experiments suggest c-Met as a key regulator of PARP inhibitor response, the researchers wrote. And they further concluded that c-Met expression may be a predictive marker for identifying resistance to PARP inhibitors and for identifying which patients should receive the PARP/c-Met inhibitor combination.