HONG KONG – In a landmark study, Singapore-based researchers have identified a novel kinase feedback loop controlling autophagy in common RAS-driven cancers and have shown that combining a kinase inhibitor with an agent that prevents autophagy may offer an effective new approach to treating such tumors.

Global mortality from cancer is predicted to continue rising, with an estimated 12 million deaths in 2030. Activating mutations in the RAS oncogene occur in 20 percent to 25 percent of all human tumors and in up to 90 percent of specific tumor types, but such activating mutations have been difficult to target therapeutically.

However, because mutations on the RAS family of proto-oncogenes are so commonly found in human cancers, it would appear likely that any pharmacological approach that restricted RAS activity might be a potential means of inhibiting certain types of cancers.

"RAS mutations are among the most common cancer-driver mutations in the world," said senior study author David Virshup, a professor and the director of the Cancer and Stem Cell Biology Programme at Duke-National University of Singapore Graduate Medical School (Duke-NUS). "RAS mutations are drivers in colorectal, pancreatic and bladder cancers."

A process of self-degradation and turnover of cellular components, autophagy is known to play a complex role in cancer pathophysiology. While evidence exists that autophagy may support tumor growth and cell survival, it can also contribute to tumor suppression and have antisurvival characteristics in different cellular systems.

In the Singapore study, which was published in the April 1, 2015, edition of The Journal of Clinical Investigation, researchers led by Virshup and Jit Kong Cheong, who is a research fellow with the Cancer and Stem Cell Biology Programme at Duke-NUS, identified a new signaling pathway that regulated cancer autophagy.

Blockade of that intracellular pathway with a therapeutic regimen comprising malaria drug chloroquine combined with a casein kinase 1 alpha (CK1-alpha) inhibitor was shown to prevent the growth of colon and bladder cancers in both RAS-driven cancer cells and murine xenograft models.

"Chloroquine is an FDA-approved drug that is safe and fairly well understood," said Virshup, noting that "chloroquine is widely used to block autophagy, as it inhibits the acidification of autophagic vesicles," which are central to the process.

The Duke-NUS researchers further demonstrated that mutant RAS controls autophagy via a CK1-alpha-dependent feedback loop. To sustain growth and prevent the autophagy of cancer cells, mutant RAS produces CK1-alpha, a highly active protein kinase, which the researchers identified as being a therapeutic target in RAS-driven cancer cells.

A combination of CK1-alpha blockade by the experimental CK1 inhibitor, D4476, and inhibition of autophagy by chloroquine, was then tested and found able to effectively treat RAS-driven human colon and bladder tumors grown in laboratory mice.

"We used subeffective doses of each agent," Virshup said. "Alone, they did not affect tumor growth much, but in combination they synergized to block growth of the cancers."

"To our knowledge, this is the first report that shows the combined pharmacological targeting of CK1-alpha and autophagy can be used to combat these types of cancer," said study first author Cheong. "Our findings provide the mechanistic basis of exploring combination therapies involving pharmacological targeting of CK1-alpha and autophagy."

The researchers speculated that the new combination therapy could help to slow down or cure some human cancers with mutant RAS, such as those that originate from the colon and the bladder. They also suggest that patients with pancreatic cancers and some lung cancers may benefit from the combination, given that the RAS oncogene is frequently mutated in those cancers.

"This is an exciting lead. We hope to identify more potent and specific inhibitors of CK1-alpha to combine with autophagy inhibitors," said Virshup, adding, "More effective autophagy inhibitors are in development . . . that will likely replace chloroquine."

Moreover, "D4476 is not a good drug, but it is a useful tool compound. We look forward to the development of good drugs to inhibit CK1-alpha before moving to human studies," he told BioWorld Today.

"If these drug combination therapies are effective in rigorous clinical trials, they may be effective in patients with cancers that carry activating mutations of the RAS oncogene," Virshup said. In the future, "we will seek to understand more about how RAS activation regulates CK1-alpha, and to extend these findings to other cancers."