Dual inhibition of autophagy and KRAS signaling shows promise in mouse models of pancreatic cancer, prompting trials in human patients.

Dual inhibition of the cell's recycling process and the KRAS pathway may help salvage two drug strategies that have each failed to work as monotherapies for pancreatic cancer.

Reporting in Nature Medicine, two research teams independently showed that concurrent treatment with an inhibitor of MEK or ERK—two nodes in the KRAS-mediated MAPK cascade—and a form of chloroquine could stunt cancer growth in human cells and in mouse models of pancreatic ductal adenocarcinoma (PDAC). An antimalarial drug, chloroquine targets lysosomes to indirectly block the last stage of autophagy.

“This is an important therapeutic strategy,” says Channing Der, PhD, of the University of North Carolina at Chapel Hill, who led one of the studies. “Not only was the combination synergistic,” he notes, “but it resulted in cell death.”

The discovery that PDAC is typically driven by the oncoprotein KRAS and also by autophagy, a metabolic process that enables the cell to recycle its own parts for energy, led clinicians to evaluate the potential of drugs targeted at both of these pathways. As monotherapies, however, neither approach offered much clinical benefit to patients.

That lack of response can now be explained by the observation that tumors compensate for inhibition of MAPK signaling by ramping up autophagic activity. “It was absolutely night and day: No matter where we blocked the MAPK pathway in various different pancreatic cancer cell lines, we saw this striking upregulation of autophagy,” says Martin McMahon, PhD, of the University of Utah in Salt Lake City, who led the other study.

Der and his colleagues showed that disrupting MAPK signaling suppresses glycolysis and mitochondrial function, and that autophagy serves as a backup source of energy to ensure metabolic fidelity. Adding an autophagy inhibitor, such as chloroquine or hydroxychloroquine, to the mix choked off this adaptive response.

Each team studied xenograft PDAC models, treating the mice with the MEK inhibitor trametinib (Mekinist; Novartis) or the ERK inhibitor SCH772984 (Merck) plus chloroquine or hydroxychloroquine. This dual therapy more effectively blunted tumor progression and extended survival than either agent alone. McMahon's group also demonstrated that the combination shrank tumors in mouse models of NRAS-mutated melanoma and BRAF-mutated colorectal cancer.

Both papers are “well done,” says Nabeel Bardeesy, PhD, of the Massachusetts General Hospital Cancer Center in Boston, MA, who was not involved in either study. “All the mechanistic data is there for a rational approach to combine these drugs in the clinic.”

McMahon's colleague Conan Kinsey, MD, PhD, has already begun testing the strategy in patients. Prompted by the laboratory data, last year Kinsey administered trametinib plus hydroxychloroquine on a compassionate-use basis to a 68-year-old patient with metastatic pancreatic cancer who was refractory to all standard therapies and likely had only about a month to live.

The treatment shrank the man's tumor burden by about 50%—and “the best part,” says Kinsey, “is he did have a very good quality of life.” In his final months, for example, the man and his wife went hiking near the Grand Canyon. The patient ultimately died about 7 months after treatment, but his partial response inspired Kinsey to launch a phase I trial to further evaluate the combination strategy with increasing doses of hydroxychloroquine. That study has enrolled three patients so far, with no dose-limiting toxicities.

Meanwhile, Der's team is working with David Fogelman, MD, and his colleagues at The University of Texas MD Anderson Cancer Center in Houston, to initiate a similar clinical trial for patients with PDAC to test the MEK inhibitor binimetinib (Mektovi; Array BioPharma) plus hydroxychloroquine. Other groups have trials involving MEK inhibitors and hydroxychloroquine that are ongoing or will soon launch for BRAF- and NRAS-mutant melanoma as well. –Elie Dolgin