黑料吃瓜资源

If there鈥檚 one thing cancer knows, it鈥檚 growth. Over the last two decades, scientists have observed that many cancers progress by activating a set of proteins called YAP and TAZ, which control cell growth and organ size. When left uncontrolled, YAP/TAZ can lead to tumor formation. So, if you鈥檙e looking for new drug targets, why not start there? Targeting them directly, while possible, remains a challenge. Now, 黑料吃瓜资源 Professor Christopher Vakoc and postdoc Olaf Klingbeil have found a workaround. They鈥檝e successfully tested their new approach in the lab against some of the most common and deadly cancers.

Previous research aimed to target YAP/TAZ molecular interactions and directly inhibit their tumor-promoting function. Vakoc鈥檚 team wanted to find another way to go after them. Using a CRISPR screening strategy, they discovered that YAP and TAZ rely heavily on a second set of proteins called MARK 2 and MARK 3. Rather than interfering with the functions of YAP/TAZ directly, targeting MARK 2/3 reactivates their natural 鈥榦ff鈥� switch, called the Hippo signaling pathway.

鈥淲e found a way to engage YAP/TAZ earlier,鈥� Klingbeil says. 鈥淢ARK 2/3 inhibition can reactivate a suppressor pathway normally used by healthy cells, thereby preventing them from going to the nucleus and being active.鈥�

Last year, Vakoc鈥檚 team transformed rhabdomyosarcoma cells into healthy muscle cells鈥攁 major advancement. However, this treatment strategy, known as differentiation therapy, is still a long way from the clinic. MARK 2 and MARK 3, on the other hand, are druggable targets, and their activity in a wider range of tumors will hopefully generate interest among pharmaceutical companies. Vakoc explains:

鈥淭his is a target for rare pediatric sarcomas that we鈥檙e very passionate about trying to solve. It鈥檚 also relevant in breast cancer. It鈥檚 relevant in lung cancer. It鈥檚 relevant in pancreatic cancer. Some of the most common human cancers and uncommon human cancers share this addiction to YAP/TAZ.鈥�

Vakoc and Klingbeil found that by reactivating YAP/TAZ鈥檚 off switch, tumors don鈥檛 just stop growing. They actually shrink, and the cancer begins to disappear. The Vakoc lab now has a new drug target in its sights. In time, that could mean more effective treatments for thousands of patients and new hope for parents who want only to see their kids grow up healthy and cancer-free.

Written by: Communications Department | [email protected] | 516-367-8455

Funding

The Pershing Square Foundation, Sohn Conference Foundation, Simons Foundation, Thompson Foundation, Christina Renna Foundation, The Mary Ruchalski Foundation, Friends of T.J. Foundation, Michelle Paternoster Foundation, Daniela Conte Foundation, Maddie鈥檚 Promise Foundation, German Research Foundation, Lustgarten Foundation, CSHL-Northwell Health Affiliation, Northwell Health Tissue Donation Program, 黑料吃瓜资源 Association, National Institutes of Health

Citation

Klingbeil, O., et al., 鈥淢ARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer鈥�, Cancer Discovery, July 26, 2024. DOI:

Core Facilites

鈥淭丑别 Mass Spectrometry Core Facility provides state-of-the-art quantitative analysis of proteins and peptides, protein-protein interactions, and post-translational modifications. The resource also offers the ability to detect lipids, metabolites, and other small molecules. The facility supports experimental design, sample preparation, LC-MS analyses, and data analysis and interpretation.鈥� 鈥� Director Paolo Cifani, Ph.D.

鈥淭丑别 Sequencing Technologies and Analysis Shared Resource provides access to an array of high throughput Next Generation Sequencing (NGS) technologies. We offer cutting-edge technology alongside convenient in-house services for a broad range of genetic analysis.鈥� 鈥� NGS Director Sara Goodwin, Ph.D.