Key protein identified that helps prevent lung cancer tumors from being destroyed
Eliminating the protein Mcl-1 could make radiation and chemotherapies more effective in treating the most common and deadly of all cancers, non-small cell lung cancer (NSCLC). Mcl-1 helps to enable NSCLC to survive radiation and drug treatments.
NSCLC makes up about 85% of the nearly 160,000 Americans expected to die this year from lung cancer, which by far kills more patients than any other type of cancer. NSCLC accounts for more than 1 in 4 cancer deaths in the United States annually. The 5-year survival rate for NSCLC is less than 10%.
In the absence of more effective targeted therapies, most lung cancer patients currently rely on platinum-derived chemotherapeutics, such as cisplatin, or radiation therapy.
Previous studies by the Translational Genomics Research Institute (TGen) in Phoenix, Arizona, have shown that excessive activation of a cellular signaling mechanism known as TWEAK-Fn14 is linked to the survival and spread of cancer cells.
In a new laboratory study published in Molecular Cancer Research (2014; doi:10.1158/1541-7786.MCR-13-0458), the investigators found that the protein Mcl-1 helps enable TWEAK-Fn14, which in turn helps protect NSCLC tumors from being destroyed by radiation and drugs.
"Our study demonstrates that the expression of Mcl-1 is necessary to promote the TWEAK-mediated survival of NSCLC tumor cells," said lead author Timothy Whitsett, PhD, an assistant professor in TGen's Cancer and Cell Biology Division. "By deactivating Mcl-1, we believe we can give these lung cancer patients a better response to standard therapy."
Employing the drug EU-5148, laboratory researchers using lung cancer cell lines found they could block Mcl-1 function and halt the TWEAK-Fn14 cellular signaling mechanism.
The researchers stated that, "Inhibition of Mcl-1 function enhanced chemo- and radio-sensitivity in NSCLC cells. The depletion of Mcl-1 … was sufficient to abrogate the protective effects conferred on lung tumor cells by TWEAK-Fn14 signaling."
"This work positions both the TWEAK-Fn14 cellular pathway and the Mcl-1 protein as potential therapeutic interventions," said senior author Nhan Tran, PhD, an associate professor in TGen's Cancer and Cell Biology Division. "Our evidence shows that, if we can bypass these mechanisms, it will be more difficult for these lung cancer cells to evade therapies."
The study concludes that additional research of Mcl-1 and TWEAK-Fn14 mechanism is needed, eventually leading to clinical trials and more effective treatments that could reduce lung cancer mortality.
The drug EU-5148 was provided by Eutropics Pharmaceuticals, based in Cambridge, Massachusetts.