‘Druggable’ cancer target found in pathway regulating organ size

Inactivating NUAK2 curbs cell proliferation in liver cancer
Reducing cancer proliferation: A small molecule that inactivates NUAK2, part of the Hippo/YAP pathway, reduces the number of cancerous cells in the mouse liver. (WEI-CHIEN YUAN/BOSTON CHILDREN’S HOSPITAL)

It’s known that cancer involves unchecked cell growth and that a pathway that regulates the size of organs, known as Hippo, is also involved in cancer. It’s further known that a major player in this pathway, YAP, drives many types of tumors. What’s been lacking is how to turn this knowledge into a practical cancer treatment. In a study published today in Nature Communications, researchers at Boston Children’s Hospital identify a target downstream of YAP, called NUAK2, and show that it can readily be inactivated with a small molecule.

“The Hippo pathway, and especially YAP, has been hard to target with drugs,” says senior study author Fernando Camargo, PhD, of Boston Children’s Stem Cell Research program. “This is the first demonstration of a ‘druggable’ molecule that could be targeted in any type of tumor driven by YAP.”

Although the study involved liver cancer, the findings could be relevant to many YAP-driven oral cancers, head and neck squamous carcinomas, pancreatic cancers, ovarian cancers and squamous cell skin cancers, Camargo believes. The team hopes to test that in future studies.

Finding a druggable cancer target

Yuan and Camargo (PHOTO: MICHAEL GODERRE)

YAP is a transcription factor, a type of target that’s been considered “undruggable,” since transcription factors lack structural features that enable a drug to bind to them. YAP in turn regulates the activity of many other genes. Wei-Chien Yuan, PhD, in Camargo’s lab set out to identify these genes, in hopes of finding something else to target.

To find what genes YAP influences, Yuan combined several assays in human liver cancer cell lines and a mouse model of liver cancer. She found 14 candidate genes, then narrowed her search to kinases, enzymes that are especially amenable to being targeted with drugs. In the end, just one emerged: NUAK2.

In further experiments, the team showed that NUAK2 (a.k.a. sucrose nonfermenting [SNF1]-like kinase, or SNARK) is critical for YAP-driven growth in human cancer cells and for liver cancer proliferation in mouse models.

Finally, they showed that a small-molecule compound that inactivates NUAK2 strongly curbed YAP-driven cancer cell proliferation and liver overgrowth.

Targeting NUAK2 has an added benefit, says Camargo, who is also affiliated with Boston Children’s Division of Hematology/Oncology and the Harvard Stem Cell Institute. “It feeds back to further activate YAP itself, so inhibiting NUAK2 further decreases activity of YAP – which is exactly what you want.”

Future plans

Camargo, Yuan and their colleagues now hope to extend their findings.

“We know that inhibiting NUAK2 works in liver cancer,” says Camargo. “We now need to see if the same mechanism is in play in other cancers.”

They also plan to modify their small molecule, originally synthesized in the lab of Nathanael Gray, PhD, at the Dana-Farber Cancer Institute.

“We want to see if we can make the compound more selective,” says Yuan, first author on the paper. “It has other nonspecific targets, so we need to modify it to make it usable.”

Hippo and YAP: A growth mindset

The story of YAP began over a decade ago with the discovery of the size-control pathway Hippo. It got this name because manipulating the pathway in fruit flies led to growth of enormous tumors, oversized eyes and wings eight times the normal size. Larger animals with defects in Hippo also have overgrown body parts. More recently, Camargo showed that activating YAP can quadruple the size of a mouse liver. Hippo and YAP have since became of interest to cancer researchers.

The current study was supported by the National Institutes of Health, the Pew Scholars Program, the Taiwan National Science Council, the National Cancer Center and the Swiss National Science Foundation. See the paper for a full list of authors and affiliations.

Read more about research in Camargo’s lab and more cancer stories.