An NCI-designated Comprehensive Cancer Center
By Elise Lamar | December 7, 2017
Cancer researchers agree that precision medicine approaches to eradicate specific tumor types are superior to previous one-size-fits-all treatments. However, developing targeted anti-cancer drugs first requires the hard work of searching for molecular markers, known as biomarkers, which identify those tumor types in order to deploy the appropriate intervention.

Such efforts have paid off in successful treatments for several cancers, among them breast tumors, where the presence of biomarkers like mutant BRCA or HER2 genes guides the choice of therapy. However, targeted interventions have not yet made solid inroads against lung cancer, which remains the No. 1 cancer killer in the U.S. and the second most common cancer in both men and women.

Ravi Salgia, M.D., Ph.D., the Arthur & Rosalie Kaplan Endowed Chair in Medical Oncology at City of Hope and associate director for clinical sciences, wants to change this situation by identifying biomarkers of lung cancer subtypes, among them the predominant form known as nonsmall cell lung cancer (NSCLC), whose overall morbidity and mortality has remained unchanged for 25 years.

His paper published in a recent online issue of Scientific Reports, a Nature research journal, reveals a novel and promising link between two NSCLC biomarkers. The study suggests that genetic evaluation of both — one a cancer "big gun" known to drive lung tumor development, and the other a NSCLC candidate gene — might help oncologists match patients with effective drug interventions against specific forms of NSCLC.

"NSCLC is a very heterogeneous disease," Salgia said. "Although we already have a number of targeted therapies, drug resistance eventually emerges when the disease becomes metastatic. Thus, identifying additional therapeutics could ultimately lead to a cure."

The new paper's major player is a cell surface protein called MET, which when damaged (mutant) or overly abundant provokes the out-of-control growth characteristic of many solid tumors. In fact, ample evidence implicates inappropriate MET activity with growth and metastasis in 25 to 75 percent of NSCLC cases. Accordingly, patients whose tumors show abnormally high numbers of MET receptors have poor prognoses.

Prior to this work, investigators had developed MET inhibitors (among them, crizotinib or cabozantinib) as anti-cancer therapies. These drugs effectively halt cancer-causing MET activity in some cases but have proved only partially effective in clinical trials against NSCLC. A critical question for oncologists was how to predict which patients would respond favorably to them.

Salgia's team addressed this by correlating expression of MET with that of another biomarker called CBL, a factor his lab previously found to be mutant in some NSCLC tumors. The new study suggests that cancer-promoting MET activity is in some way influenced or modulated by whether CBL is mutant. As evidence, they report that NSCLC cells harboring both CBL mutations and overactive MET are more readily eradicated by a MET inhibitor than are MET-positive tumor cells exhibiting normal (nonmutant) CBL.

All of these experiments suggest that NSCLC tumors displaying normal CBL may be more resistant to eradication by MET inhibitors than those harboring mutant CBL. A molecular explanation for these findings awaits future experiments. Biochemically, close association with CBL makes other proteins less stable, suggesting that CBL might directly alter MET protein levels. Alternatively, CBL might regulate MET indirectly through an as yet unknown factor.

Whichever molecular scenario proves true, Salgia says it is now time to consider CBL mutational status when implementing effective treatments for NSCLC.

"Our work suggests that we should consider whether the CBL gene is damaged in designing trials of particular MET inhibitors," said Salgia. "In the future, it will also be important to broaden these studies not only to NSCLC but to other cancers, both in preclinical and clinical investigations."

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