New Combo Therapy Approach to Combat Drug Resistance

A new study shows how to overcome drug resistance after exposure to certain targeted cancer therapies known as RAF and MEK inhibitors.

In a recent press release, Luping Lin, PhD, a postdoctoral fellow at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, and colleagues from cancer research centers in New York, Boston, Houston, Spain, Italy, and Germany identified a protein called YAP that contributes to resistance of MEK and BRAF inhibitors. The protein is part of a pathway that promotes survival and resistance in the presence of these targeted agents.

The study is published in the February 2015 issue of Nature Genetics.  

BRAF inhibitors dabrafenib (Tafinlar) and vemurafenib (Zelboraf) are approved by the US Food and Drug Administration (FDA) for treatment of metastatic melanoma that harbors a V600E mutation in the BRAF gene. The combination of dabrafenib plus trametinib is also approved as a therapy for metastatic melanoma tumors that express either a V600E or V600K mutation. MEK and BRAF inhibitors are also being studied for a variety of other tumor types. Despite cancers responding to these--and most targeted agents--response is transient, and most patients eventually develop resistance. Additionally, those tumors that also harbor a mutation in the RAS gene are inherently resistant to both BRAF and MEK inhibitors.

Resistance mechanisms can either be in the same gene or signaling pathway, or through an alternative pathway.

Lin and colleagues conducted a genetic screen in BRAF-mutated tumor cells, uncovering that the combination of a YAP pathway protein, BCL-xL, BRAF, and MEK inhibitors resulted in synthetic lethality for both BRAF-mutated tumor cells as well as RAS-mutated tumors. The authors found that higher levels of YAP in BRAF V600E-mutated melanomas and lung tumors indicate a worse response to MEK and RAF inhibition. Moreover, patients whose tumors had relatively higher YAP levels were more likely to have an incomplete response when treated with either a BRAF or MEK inhibitor, and those that developed resistance had higher YAP levels. 

The authors sought to identify proteins whose activity, when decreased, allowed the BRAF inhibitor vemurafenib to more effectively kill tumor cells. Using lung cancer cells with a BRAF mutation, the authors combined a knock down of one of 5,000 genes with vemurafenib therapy. Knocking down the activity of YAP enhanced the effectiveness of vemurafenib. Similarly, lung cancer cells with diminished YAP activity were also more sensitive to the MEK inhibitor, trametinib (Mekinist).  The researchers saw similar results with cell lines from human colon and thyroid cancers as well as melanoma.

The study also identified components of the YAP pathway including BCL-xL that functions in the cellular apoptotic pathway.

Both vemurafenib and trametinib were more effective in mouse models with melanoma or colon cancer when the activity of YAP was dampened. Likewise, RAS-mutated pancreatic cancer, lung Cancer, and melanoma mouse models with decreased YAP activity were more responsive to trametinib.

Both clinical and preclinical studies of targeted cancer therapies have led cancer researchers to posit that combination therapies given upfront is a better strategy to block the ability of cancer cells to develop resistance, or at least to stall the cells’ ability to develop ways to bypass inhibition. This strategy is thought to lead to longer-lasting responses compared to using targeted therapies sequentially when a cancer stops responding to a single agent.

"Instead of trying to figure out why patients have developed resistance after it has emerged, we need to decipher what survival tactic tumor cells will be most dependent on when they are challenged with targeted therapy," said study author Trever Bivona, MD, PhD, UCSF assistant professor of medicine and part of the UCSF Helen Diller Family Comprehensive Cancer Center in a statement." We want to learn how to wipe out that alternative survival pathway at the beginning of therapy--to pull the rug out from under those cells right away."

YAP was originally studied as a protein involved in organ development in the fruit fly, underscoring the importance of basic science research and its impact on human health, Bivona noted.