Simultaneous inhibition of two proteins, FAK and MDM2, may have therapeutic applications against mesothelioma. A recent study showed that the proteins prevent malignant cells from activating mechanisms involved in cell death, and activate those involved in proliferation.
Currently, conventional chemotherapies and radiation therapy show limited impact against mesothelioma. Scientists agree that new and more effective agents are required to substantially improve patient survival.
For the new study, researchers used cell lines and primary tumors extracted from mesothelioma patients to focus on understanding how the protein FAK is involved in mesothelioma progression. FAK was found to be highly expressed in all tumors, which correlated with decreased protein levels of the tumor suppressor gene p53.
p53 is involved in cell mechanisms that lead to the death of defective cells; it’s activity stops the formation of tumors. Nearly half of human tumors acquire inactivating mutations of the protein, which allows them to keep growing without mechanisms that verify whether the tumor cells are defective or not.
Although mutations in p53 are not common in mesothelioma, preventing the protein from being produced or activated may have a role in the progression of the disease.
When the researchers inhibited FAK, the levels of p53 raised and its activation increased up to three times in the mesothelioma cells, which led to a decrease in cell viability and inhibition of the cell cycle. Combining FAK inhibition with stopping MDM2, a protein involved in the degradation of p53, had a synergistic effect in cell viability and resulted in an 80 to 90 percent reduction in the viability of the tested cell lines.
Studies have shown that high levels of p53 in mesothelioma enhance the effectiveness of first-line chemotherapy regimens containing Platinol (cisplatin) or Alimta (pemetrexed) — which suggests that inhibitors of FAK and MDM2, in combination with those therapies, might bring about better outcomes for mesothelioma patients.
“FAK and MDM2 inhibition together induced greater p53 expression, cell apoptosis, anti-proliferative effects, and cell cycle arrest, as compared with either intervention alone,” the researchers wrote. “These findings highlight novel therapeutic opportunities in mesothelioma.”