Scientists at the University of California San Francisco (UCSF) have homed in on identifying the mechanism that some cancers cells take advantage of to circumvent commonly used drug regimens. The UCSF scientists believe that the results from this study may aid in the discovery of new combination therapies that could overcome resistance to individual drugs that is becoming increasingly prevalent.   

Investigators found that a protein called YAP, which was previously identified to play a role in the growth and size regulation of organs, has a critical function in the emergence of cancer drug resistance. The results from this study are published today in Nature Genetics in an article entitled “The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies”.

Current cancer drugs that target specific genetic mutations have been successful, but there are a significant number of patients that will develop resistance to these therapies. These resistance mechanisms are thought to arise because cancer cells seek alternative survival pathways that are beyond the reach of the drug target.

For patients who have developed resistance, physicians can switch to a different chemotherapy strategy, but most researchers and clinicians believe that blocking the pathway that leads to the cancer cell circumventing the primary drug is a better tactic. 

“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 Trever Bivona, M.D., Ph.D., UCSF assistant professor of medicine at UCSF and senior author of the study. “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.”

Dr. Bivona and his team used short-hairpin RNAs (shRNAs) to genetic silence the activity of more than 5,000 proteins in a lung cancer cell line that was prone to drug resistance due to a mutation in the proto-oncogene BRAF. When the researchers concomitantly treated the cells with the BRAF inhibitor vemurafenib and shRNAs they were able to quickly determine which proteins were involved in allowing the cells to avoid the drugs mechanism of action. 

The results showed that the YAP protein was critical in the cells ability to tolerate vemurafenib, as all six shRNAs that targeted YAP greatly enhanced the efficacy of the drug on BRAF mutant cancer cells. Moreover, the researchers saw similar results when treated the mutant cells with trametnib, which targets the BRAF activated protein MEK.

As an additional level of validation to their in vitro results, the USCF researchers found similar effects when melanoma or colon cancer cells were injected into mice. When they silenced YAP in the mice and treated them with vemurafenib and trametinib, the overall survival rate was greater than without the shRNA intervention

Dr. Biovona concluded that, “this is the first paper to establish that YAP is a bona fide mechanism of resistance to RAF and MEK inhibition and it's exciting to contemplate and plan what we may be able to do with this knowledge to help cancer patients by improving their precision treatment.”

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