Colon cancer cells with the cell nuclei stained red and the protein E-cadherin stained green. Credit: NCI Center for Cancer Research.
As many as 50 percent of human cancer cases — across a wide variety of tissues — involve defects in a common cellular growth signaling pathway. These defects have so far defied most attempts to develop targeted therapies, leading some in the field to conclude that they may be “undruggable.” Now researchers at UC San Francisco and Redwood City–based Revolution Medicines, Inc, have identified a new strategy for potentially treating a subset of such intractable cancers by decoupling the entire RAS / MAP Kinase (MAPK) signaling pathway from external growth signals.
In a study published August 13, 2018, in Nature Cell Biology, the researchers showed that an experimental compound recently discovered by Revolution Medicines interferes with the first steps of the RAS / MAPK pathway and dramatically slowed cancer growth in lung, skin, colon and pancreatic cancer cell lines as well as human lung cancers grown in animal models. Based on these results, Revolution Medicines aims to rapidly advance this approach into clinical trials in human patients using a proprietary drug candidate called RMC-4630.
“RAS / MAPK is one of the most important cancer signaling pathways, but so far most attempts to develop targeted drugs against this pathway have ended in failure, which has led some people to start calling it a ‘Holy Grail’ of cancer therapy," said study senior author Trever Bivona, MD, PhD, a UCSF Health clinical oncologist. “Now, for the first time, we think we have a general strategy that could work against a subset of RAS / MAPK–driven cancers.”
The RAS / MAPK pathway (also known as the MAPK / ERK pathway), which plays a central role in telling normal cells when to grow and divide, works via a Rube Goldberg–like cascade of protein interactions. It begins with an “upstream” growth signal from outside the cell binding to a receptor protein on the cell surface, which activates the protein RAS inside the cell, which in turn triggers a sequence of steps (RAS recruits RAF, RAF activates MEK, MEK stimulates MAPK) that ultimately direct a wide variety of “downstream” growth-promoting genetic programs in the cell nucleus. At the same time, regulatory proteins such as the tumor suppressor NF1 keep the volume of growth signaling through the RAS / MAPK pathway within a healthy range.
Mutations in one or a combination of proteins involved in this cascade can send cellular growth into overdrive, leading to tumor formation. However, most attempts to develop drugs targeting individual defects in the RAS / MAPK pathway or to block its downstream effects have failed — either because the pharmacology of affected proteins makes them too difficult to drug, or because patients’ cancers were able to quickly develop resistance to treatment through alternative arms of the RAS / MAPK pathway.
But recent studies have suggested a new opening for potential therapies, Bivona says. Scientists have long thought that cancer-associated RAS / MAPK defects always involve one of the pathway’s proteins getting jammed in its pro-growth position so that cells no longer respond to normal growth signals and become locked in a mode of constant growth. In contrast, recent research has shown that some of cancer-linked mutations merely make the associated protein hypersensitive to normal growth signals — essentially turning up the volume of the RAS /MAPK signaling pathway as a whole. In cancers driven by such mutations, Bivona and others reasoned, blocking upstream growth signaling at the source could halt cancers’ growth.
Bivona and colleagues have now tested this hypothesis — demonstrating that the growth of multiple cancers can be slowed by suppressing RAS / MAPK signaling using a novel experimental compound that targets an enzyme and scaffolding molecule called SHP2.