An international team of researchers has published data they believe could dramatically boost the effectiveness of chemotherapy for malignant mesothelioma.
Malignant mesothelioma is a highly lethal, asbestos-linked cancer. One of the reasons it is so difficult to cure is that it is resistant to all of the standard cancer drugs.
Now, scientists with the University of New Mexico, the University of Kansas, and Semmelweis University in Hungary say they managed to make mesothelioma cells much more susceptible to chemotherapy drugs in the lab by also administering a drug designed to inhibit cellular expression of an enzyme called AXL.
Enzyme “Protects” Mesothelioma Cells from Chemotherapy
AXL is a tyrosine kinase inhibitor expressed on the surface of cells. It is one of the mechanisms through which cells – including mesothelioma cells – try to “protect” themselves from attack by outside threats, including chemotherapy drugs. According to the new study, AXL kinase expression is relatively high in mesothelioma patients, compared to those with other cancers.
In addition, reactive oxygen species (ROS), molecules produced by both asbestos exposure and chemotherapy, can trigger even higher AXL expression. The team believes that this reaction may help explain why chemotherapy for mesothelioma is often not very effective.
Defeating Mesothelioma Chemotherapy Resistance
Recognizing that ROS are an inevitable part of both having malignant mesothelioma and undergoing chemotherapy with Alimta and cisplatin (the standard combination), the researchers focused on a way to counteract their impact on AXL.
Their research focused on an AXL inhibitor called BGB324. Clinical studies in healthy volunteers and cancer patients have found BGB324 to be well-tolerated with a “favorable safety profile” in people with acute myeloid leukemia and non-small cell lung cancer. It holds orphan drug status for AML.
When researchers “knocked down” AXL in two different lines of mesothelioma cells with BGB324, the cells became more sensitive to the chemotherapy drugs. The effect was even more dramatic when the cells were pretreated with BGB324 before chemotherapy was added.
“These results demonstrate cisplatin and pemetrexed induce ROS that activate AXL, and blocking AXL activation enhances the efficacy of cisplatin and pemetrexed,” writes study author Derek B Oien, PhD, a postdoctoral fellow in the Division of Molecular Medicine at the University of New Mexico Cancer Center. “These results suggest AXL inhibition combined with the current chemotherapy regimen may represent an effective strategy to enhance the efficacy of chemotherapy in mesothelioma.”
The authors say this is the first study to show how chemotherapy drugs and reactive oxygen species activate AXL and may be contributing to chemotherapy resistance in mesothelioma.
Oien, DB, et al, “Cisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy”, January 11, 2018, Frontiers in Pharmacology