Target Acquired – Innovita Research

Cancer involves unchecked cell growth. A biological pathway known as Hippo, which regulates organ size, is also involved in cancer, and a major player in this pathway, YAP, drives many types of tumors.

Now, researchers at Harvard Medical School and Boston Children’s Hospital have solved an ongoing problem: how to turn this knowledge into a practical drug target.

In a study published in Nature Communications, they show that YAP acts largely through another downstream player called NUAK2 that can readily be inactivated with a small molecule.

A small molecule that inactivates NUAK2 reduces the number of cancerous cells in a mouse liver. Image credit: Wei-Chien Yuan

“The Hippo pathway, and especially YAP, has been hard to target with drugs,” said senior study author Fernando Camargo, professor of stem cell and regenerative biology at HMS and professor of pediatrics at Boston Children’s. “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 said. The team hopes to test that in future studies.

Target practice

YAP is a transcription factor, a type of target that’s been considered undruggable because transcription factors lack structural features that enable drugs to bind to them.

But YAP in turn regulates the activity of many other genes. Postdoctoral fellow Wei-Chien Yuan in the Camargo lab, first author of the paper, set out to identify these genes in hopes of finding something else to target.

Using human liver cancer cell lines and a mouse model of liver cancer, Yuan combined several assays to zero in on what downstream genes YAP influences. She found 14, then narrowed her search to kinases, enzymes that are especially amenable to being targeted with drugs. Just one emerged: NUAK2.

Further experiments showed that NUAK2—also known as sucrose nonfermenting (SNF1)-like kinase, or SNARK—is critical for YAP-driven growth in human cancer cell lines and for liver cancer proliferation in mouse models.

Finally, the team 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, said Camargo. “It feeds back to further activate YAP itself, so inhibiting NUAK2 further decreases activity of YAP, which is exactly what you want.”

Future plans

Yuan and her colleagues now hope to extend their findings.

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

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

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

Source: HMS