Yes Signaling Pathway Implicated in Liver Cancer Development

NEW YORK (Reuters Health) – Yes, a tyrosine kinase, drove the spread and aggressiveness of hepatocellular cancer (HCC) in cells, mouse models, and an analysis of patient data.

“The good news is that Yes is pharmacologically tractable, and our pre-clinical findings provide a strong rationale for targeting Yes in advanced HCC,” Dr. Sylvain Meloche of the University of Montreal in Quebec told Reuters Health by email.

“To evaluate the clinical relevance of Yes in human HCC, we used bioinformatics to derive a gene signature predictive of Yes activity in HCC cells,” he explained. “Using clinical samples from HCC patients, we were able to show that increased Yes activity, rather than mutations in Yes or increased Yes abundance, correlates with poor survival in HCC.”

Using genetic and pharmacological interventions – specifically, the nonselective Src family kinase inhibitor dasatinib – in both cellular and mouse models of HCC, the team showed in their Science Signaling report that Yes activity was necessary for HCC cell proliferation.

Mechanistically, activating Yes in mouse hepatocytes was sufficient to induce liver tumorigenesis. Yes phosphorylated the transcriptional proteins YAP and TAZ, which led to their accumulation in the nuclei, resulting in proliferation of HCC cells and increased the tumor burden mice.

As Dr. Meloche indicated, an analysis of patient data from the Cancer Genome Atlas database showed that high Yes activity – but not increased abundance – correlated with shorter survival times.

The authors conclude, “Our findings identify Yes as a potential therapeutic target in HCC.”

Dr. Meloche added, “There are some protein kinase inhibitors that are known to inhibit Yes activity, but these compounds are non-selective and were developed for other purposes or for other clinical indications.”

“The next step,” he said, “would be to develop new Yes inhibitors that are more selective, with a better safety profile, and to identify reliable pharmacodynamic biomarkers in order to select the subset of HCC patients most likely to benefit from such compounds. Our findings should help address this challenge.”

“Yes inhibitors could also be used in combination with other targeted therapies, a possibility that we are currently exploring in pre-clinical models,” he added.

Geneticist Jessica Zucman-Rossi, Director of the Cordeliers Research Centre and Professor of Medicine at the University of Paris Descartes, commented on the study in an email to Reuters Health. “This report could be important for the clinic since the authors clearly showed in HCC cell lines an antiproliferative effect using dasatinib, a multikinase inhibitor used to treat leukemia that inhibits Yes.”

“A major question for the future is: are all HCCs in patients dependent on Yes for their progression or is this ‘oncogenic addiction’ found only in a subtype of HCC? A biomarker to predict response to an src inhibitor would be very interesting,” she said.

“Clinical trials are necessary to prove that Yes can be targeted efficiently in patient with HCC,” she said. “Results of a phase 2 clinical trial testing dasatinib in 25 HCC patients (https://bit.ly/3KFlDkM) were negative.” Like Dr. Meloche, she added, “other src kinase inhibitors could be tested alone or in combination with other anti-tumor therapies.”

SOURCE: https://bit.ly/3FX56VN Science Signaling, online January 18, 2022.

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