Duke/NUS team says new combo has promise for mutant-RAS cancers

SINGAPORE--A team of investigators from Duke and the NUS Graduate Medical School in Singapore says they've come up with a novel one-two punch directed against mutant RAS that they believe could have broad potential in fighting cancers.

According to the scientists, mutant RAS-driven cancer cells--which rely on a pathway to control autophagy, a process involved in a cell's internal nutritional status--has an Achilles heel: a protein kinase called Casein kinase 1α (CK1α). In order to thrive, mutant RAS requires CK1α. And by slamming CK1α with a new drug, an inhibitor dubbed D4476, while adding a second antimalarial drug called chloroquine that inhibited autophagy, they were able to prompt a promising response in models for mutant RAS-driven cancers. 

Jit Kong Cheong

"To our knowledge, this is the first report that shows the combined pharmacological targeting of CK1α and autophagy can be used to combat these types of cancer," said the first author on the study, Dr. Jit Kong Cheong. "Our findings provide the mechanistic basis of exploring combination therapies involving pharmacological targeting of CK1α and autophagy."

The scientists say that this approach has particular promise for cancers that begin in the bladder or colon, as well as pancreatic and lung cancers, which are often RAS-driven. And after they come up with better drug candidates, they want to try it in the clinic.

"This is an exciting lead. We hope to identify more potent and specific inhibitors of CK1α to combine with autophagy inhibitors," said senior author Professor David Virshup, who is the director of the Cancer and Stem Cell Biology Program at Duke-NUS. "If these drug combination therapies are effective in rigorous clinical trials, it may be effective in patients with cancers that carry activating mutations of the RAS oncogene."

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