Researchers Reveal the Mechanism Behind Targeted Cancer Therapy Drug Resistance

Researchers Reveal the Mechanism Behind Targeted Cancer Therapy Drug Resistance

scientistResearchers at the University of California, San Francisco (UCSF) recently published in the journal Nature Genetics their findings on a protein known as YAP and its role in the development of resistance to targeted cancer therapies. The study is entitled “The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.

Cancer drugs have been applied successfully as a therapy; however, the majority of patients eventually acquire resistance, most likely due to cancer cells adopting alternative survival strategies that are not affected by the drugs used. Administering a different targeted drug is an option, but several cancer researchers believe that it would be better to predict the possible escape paths for cancer cells and use a combination therapy of targeted drugs.

“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,” explained the senior author of the study Dr. Trever Bivona in a news release. “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.”

The team used a gene-silencing approach known as short-hairpin RNAs (shRNAs), to decrease the activity of more than 5,000 proteins present in lung cancer cells carrying mutations in the BRAF gene, which are well-known to greatly increase the risk of developing cancer.

The drug vemurafenib (Zelboraf) targets defective BRAF proteins, and researchers used it, together with specific shRNAs, to determine if the drug was more effective in the absence of particular proteins. shRNAs targeting YAP enhanced the efficacy of the drug in killing BRAF-mutant cancer cells, indicating that the YAP protein plays a role in resistance to vemurafenib.

Similar results were also observed when testing a different drug called trametinib (Mekinist) in colon cancer cells carrying BRAF mutations. About 5% to 10% of patients with colorectal cancer harbor the BRAF mutation, placing them at risk for poor treatment response and worse outcomes.

Besides BRAF, mutations on another cancer driving gene, called RAS, were also assessed. The team observed that in the presence of YAP suppression, trametinib was highly effective in killing RAS-mutant cancer cells. All these results were observed in both cell culture assays and in rodent models.

In humans, YAP was found to be highly expressed in BRAF- and RAS-mutant lung cancer and melanoma prior to treatment, and patients who develop drug resistance were found to have increased YAP levels. The team discovered that the high levels of YAP in cancer cells maintain a protein called BCL-xL, which when activated prevents cells from self-destructing.

“YAP was the number-one hit in our screening process, but it wasn’t much of a leap to think it might be promoting resistance to targeted therapy, because it had been shown to promote organ growth and cell proliferation in other organisms and systems,” said Dr. Bivona, highlighting the key role of basic biological research for human health. “So this work stood on the shoulders of very good, purely basic science.”

The team suggests that a combination of drug inhibitors would be more effective as a therapy and may overcome the problem of emergence of drug resistance in several BRAF- and RAS-mutant tumors, potentially improving patient survival. They are pursuing collaborations with pharmaceutical companies for the development of compounds that directly target YAP. As for the fact that this study is the first one to define YAP’s key role in the emergence of resistance to targeted cancer therapies, Dr. Bivona said “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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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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