Inhibiting Wnt signalling with ETC-159 reactivates the hyperactive RAS-MAPK pathway, causing cells to led undergo senescence. Many cancers are driven by activating mutations in the RAS-MAPK signalling pathway which triggers a cascade of proteins that directs cells to grow, divide and migrate. Mutations in proteins involved in this cascade can turn on genes that make this process go into overdrive, causing cells to grow out of control and aggressively invade other parts of the body. However, too much RAS-MAPK signalling causes cancer cells to prematurely age, and eventually stop growing -- a process called cellular senescence.

Publishing in Cancer Research, the Duke-NUS research team found that another important and well-known biochemical pathway, the 'Wnt' (pronounced 'wint') signalling pathway, allows some cancers to grow by dampening RAS-MAPK signalling.

The team made the discovery while investigating how Wnt proteins regulate pancreatic cancers. Scientists have long observed that genetic mutations causing Wnt proteins to be hyperactive drive many common cancers. The long-held thinking had been that this is because Wnt signalling causes cells to grow too fast. The new findings suggest this idea needs re-evaluation.

By making RAS-MAPK signalling "not too hot and not too cold," Wnt signalling enables cancers to grow steadily instead of heading towards the premature ageing that can be caused by excessive RAS-MAPK signalling. These findings support a growing awareness that cancers need a "just-right" level of RAS-MAPK signalling. Disrupting modulating signals like Wnt can cause cancers to stop growing by forcing them to undergo cellular senescence, similar to just getting old.

Assistant Professor Babita Madan, from Duke-NUS Cancer and Stem Cell Biology (CSCB) Programme, a senior co-author of the study, explained, "Using an experimental drug, ETC-159 , to stop Wnts in multiple models of human pancreatic and colorectal cancer, we found that, unexpectedly, Wnt signalling turns off as many genes as it turns on."

Digging deeper, the team made the connection between Wnt signalling and the diminished activity of the RAS-MAPK pathway. Inhibiting Wnt signalling with ETC-159 and other anti-cancer drugs actually activated RAS-MAPK signalling, while inhibiting cancer growth at the same time.

"This makes sense; while activating mutations in the RAS-MAPK pathway are common in cancer, in isolation, they cause cells to stop growing by causing senescence, a form of ageing-induced arrested cell growth," said Professor David Virshup, Director of the CSCB Programme, and also a senior co-author of the study. (Prof Virshup's seminal research on Wnts led to the development of ETC-159.) "By reining in RAS-MAPK signalling, Wnt signalling achieves Goldilocks' goal of getting it not too hot, not too cold, but just right."

One implication of this research is that it opens up additional ways to attack cancers. The traditional way is to kill cancer cells, however this new study shows that stopping cancer cell growth can be achieved by inducing senescence.

"Cancer is the second leading cause of death globally, responsible for an estimated one in six deaths. In Singapore, cancer cases have been rising over the years, and the number of people living with cancer will continue to increase ," noted Professor Patrick Casey, Senior Vice Dean for Research at Duke-NUS. "Studies like these exemplify the importance of robust fundamental science research to guide new approaches and strategies that have the potential to make a major impact on disease."

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Materials provided by Duke-NUS Medical School. Note: Content may be edited for style and length.

Journal Reference:

1. Nathan Harmston, Jun Yi Stanley Lim, Oriol Arqués, Hector G Palmer, Enrico Petretto, David M. Virshup, Babita Madan. Widespread repression of gene expression in cancer by a Wnt/β-catenin/MAPK pathway. Cancer Research, 2020; canres.2129.2020 DOI: 10.1158/0008-5472.CAN-20-2129