Silencing YAP May Overcome Resistance to Targeted Therapies

Trever G. Bivona, MD, PhD

Trever G. Bivona, MD, PhD

An international team of scientists from some of the world’s most prominent cancer centers and research universities has shed additional light on the important role of Yes-associated protein (YAP) in tumor development and in treatment response. Led by researchers at the University of California San Francisco (UCSF), the team conducted a series of experiments that helped determine how YAP signaling allows cancer cells to escape the apoptotic effects of RAF and MEK inhibitors.

First, the researchers used RNA-interference approaches to silence more than 5000 target genes one at a time, in human lung cancer cells that harbored aBRAFV600E mutation (the HCC364 cell line). They treated one group of HCC364 cells with vemurafenib (Zelboraf), a BRAF inhibitor, while another group received vehicle and served as controls.

Vemurafenib proved far more potent at killingBRAF-positive cancer cells whenYAP1in the Hippo signaling pathway was silenced. Additional investigation showed thatYAP1also mediated response to MEK inhibitors. The finding thatYAP1silencing enhanced sensitivity of cancer cells to the effects of RAF and MEK inhibitors persisted across multiple tumor types with aBRAFmutation.

The investigators also found that suppressingYAP1in tumors with aRASmutation, which promotes tumor growth through MEK-ERK signaling, increased the apoptotic effects of MEK and RAF inhibitors. This finding was especially important because no targeted therapies are available forRAS-positive tumors, and current MEK inhibitors have shown only limited activity against them. Concurrent suppression ofYAP1and RAF-MEK signaling further enhanced cell death in response to treatment with a RAF or MEK inhibitor. Additional research showed that both YAP and RAF-MEK signaling regulated expression of member protein B-cell lymphoma-extra large (BCL-xL), which may provide tumor cells with an escape mechanism when only YAP or only RAF-MEK is targeted.

Immunohistochemistry analyses and evaluation of tumor specimens for YAP expression revealed higher levels on average in tumors harboring aBRAForKRASmutation than in wild-type tumors. Baseline overexpression of YAP was observed in untreatedBRAF-positive tumors that later responded poorly to targeted therapy with a BRAF inhibitor administered alone or with a MEK inhibitor. In addition,BRAF-positive tumors with low or intermediate baseline YAP expression demonstrated higher levels of YAP after acquiring resistance to BRAF and MEK inhibitors.

Targeted Oncologyinterviewed lead author Trever G. Bivona, MD, PhD, assistant professor of medicine, UCSF, and member of the UCSF Hellen Diller Family Comprehensive Cancer Center, about the study and its implications for future treatment strategies.

Targeted Oncology (TO):Could you briefly explain the mechanism of YAP in promoting resistance to targeted drugs?

Bivona:YAP promotes resistance to RAF- and MEK- targeted therapies by acting as a parallel survival factor in cancer cells. YAP was associated with both initial and acquired resistance in our studies.

TO:Is YAP expressed in normal cells and, if so, what function does it serve?

Bivona:Yes, and it regulates organ size primarily. The roles of YAP in normal (and cancer) cells are not completely known, and this is an active area of research.

TO:How did you discover YAP and its role in resistance?

Bivona:We discovered YAP using an unbiased genetic screen to identify genes that when silenced enhanced the response to RAF-inhibitor treatment in cancer cells.

TO:Are your findings regarding YAP applicable to all cancers?

Bivona:They are applicable to many cancers, including lung cancer, melanoma, thyroid cancer, pancreatic cancer, and colon cancer and perhaps other cancers withRAForRASmutations.

TO:What are possible strategies for overcoming the YAP resistance mechanism?

Bivona:The most direct strategy is to use an inhibitor of YAP in combination with RAF- or MEK-targeted therapy as upfront treatment. Because no selective YAP inhibitors exist, another approach is to target a key protein functioning downstream of YAP in resistance. One such protein is BCL-xL, a protein for which drugs have been developed and tested in patients. But this latter approach may be limited by the toxicity of the BCL-family protein inhibitors.

TO:In the past, some oncologists have expressed concern that giving patients several of the available treatments together in the upfront setting leaves them with nothing in reserve when the patient eventually relapses. Has this perspective fallen by the wayside in this era of targeted therapy and does your discovery have any implications for this perspective?

Bivona:I think the goal remains to eradicate or indefinitely control the cancer from the outset with this combinatorial therapy approach so that one may not need to worry about additional cancer treatments in the future. That may sound ambitious, but there is precedence in other diseases.

TO:Your study mentioned that the level of YAP expression varied between patients. Do you have any theories as to why some patients would have higher YAP levels than others?

Bivona:We are unsure at this time, and it is an active area of investigation.

TO:Do you think there may come a time when patients are tested for YAP expression levels before treatment?

Bivona:Yes. Indeed, we found that increased YAP was a biomarker of poor response to RAF-MEK inhibitor treatment. Thus, YAP may be a useful new predictive biomarker of response in patients.

TO:Is anyone looking at developing YAP or BCL-xL inhibitors?

Bivona:I am sure, but we hope our work stimulates or accelerates this process.

Reference

Lin L, Sabnis AJ, Chan E, et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.Nat Genet