Combination Drug Therapy May Prevent Tumors From Sidestepping Kinase Inhibitors

New research has shed light on how some tumors continue their growth despite treatment with kinase inhibitors, and on how a combination of drugs can yield much better results. This study, done in mice, will help scientists overcome the bypass system that has allowed tumors to resist kinases.1

"We've discovered a previously unappreciated mechanism involved in resistance to targeted therapeutics," said Douglas Lauffenburger, PhD, the Ford Professor of Bioengineering and head of Massachusetts Institute of Technology's Department of Biological Engineering, Cambridge, Massachusetts, and lead in the study.

"Its presence appears to be associated with poor response to some kinase inhibitors in clinical patients. And we've demonstrated that in mice adding a drug against this resistance mechanism allows the original targeted drug to work when otherwise it wouldn't."

Kinase inhibitors disrupt cell signaling pathways that stimulate cells to grow, proliferate, or become invasive. They are often used to treat breast, ovarian, and other cancers, typically when a tumor is overexpressing a cancer-driving protein such as epithelial growth factor receptor (EGFR).

Notably, kinase inhibitors often fail even when they should work. These failures are attributed to known genetic mutations in only half of cases.

Lauffenburger's research team suspected a backup pathway was helping cancer cells to sidestep the effects of kinase inhibitors. They found that giving a kinase inhibitor to shut off the EGFR pathway also led to shutting off proteases and allowing backup pathways to take over.

The research suggests that patients whose tumors have a strong backup pathway could benefit from a combination therapy that addresses the EGFR pathway and the secondary pathway. A candidate drug that is an AXL inhibitor is now in clinical trials.

The research also suggests that the backup system could help treatment teams identify which patients have tumors that will be more resistant to kinase inhibitors.


1. Miller MA, Oudin MJ, Sullivan RJ, et al. Reduced proteolytic shedding of receptor tyrosine kinases is a post-translational mechanism of kinase inhibitor resistance [published online ahead of print March 16, 2016]. Cancer Discov. doi:10.1158/2159-8290.CD-15-0933.

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