New Study Reveals How Some Cancer Drugs Don’t Work

Sharon Moore February 10, 2015

A group of researchers from UC San Francisco found that a protein which drives the growth of organs during development and regulates their size in adulthood, plays a key role in the emergence of resistance to targeted cancer therapies.

Though cancer drugs aimed at specific genetic mutations have had some success in recent years, most patients who have a good initial response eventually develop resistance to these therapies, most likely because cancer cells engage alternative survival mechanisms that lie outside the biological pathways targeted by the drugs.

Though oncologists have the option of switching to a different targeted drug after resistance takes hold, many cancer researchers believe that a better strategy would be to forestall cancer cells’ eventual escape routes by using customized combinations of targeted drugs at the outset of therapy.

"Instead of trying to figure out why patients have developed resistance after it has emerged, we need to decipher what survival tactic tumour cells will be most dependent on when they are challenged with targeted therapy," said the senior author of the study, Trever Bivona, MD, PhD, UCSF assistant professor of medicine and a member of the UCSF Helen Diller Family Comprehensive Cancer Canter (HDFCCC). "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."

For the study, researchers used a gene-silencing tool called short-hairpin RNAs (shRNAs) to tamp down the activity, one-by-one, of more than 5,000 proteins in lung cancer cells that carried cancer-causing mutations in a gene called BRAF. By simultaneously treating the cells with the cancer drug vemurafenib (Zelboraf), which specifically targets faulty BRAF proteins, the researchers were able to determine whether the drug was more effective when the action of other particular proteins was blocked.

These experiments quickly and decisively fingered YAP in vemurafenib resistance, as all six YAP-directed shRNAs employed by the scientists significantly enhanced the drug’s effectiveness at killing BRAF-mutant cancer cells. The researchers saw similar results with trametinib (Mekinist), which targets a BRAF-activated protein called MEK. Working with other types of cancer cells carrying BRAF mutations, including cells from human melanoma, colon, and thyroid cancers, the researchers again found that suppressing YAP enhanced the effectiveness of both vemurafenib and trametinib.

The collective lab-dish results held up in experiments with animal models in which cells from melanoma and colon cancer were injected under the skin of mice and formed tumours: vemurafenib and trametinib were far more effective in treating these tumours when YAP had been suppressed.

Bivona emphasized that YAP’s role in organ development was first discovered in the fruit fly Drosophila, and he sees the research as a testament to the importance of basic biological research to improving human health. "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," he said. "So this work stood on the shoulders of very good, purely basic science."

The new study was published in the journal Nature Genetics.

Source of this article: The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies