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Taking an Indirect Route to Stopping Pancreatic Cancer

KRAS Oncogene Is a Problematic Target So Researchers Are Trying Workdarounds

If cancer were a personality, it would win accolades for resilience. When a drug blocks a cancer cell's main survival pathway, the cell avoids the obstacle by taking different pathways or detours to save itself. This tactic is one of the key challenges researchers face when seeking effective therapeutics to combat pancreatic ductal adenocarcinoma.

But a group of researchers at Cold Spring Harbor Laboratory has now found a way to tackle this problem. Their findings—which were in mice and therefore should have “preliminary” written on them in big, red letters—were published in the journal Clinical Cancer Research.

More than 90% of pancreatic cancer patients carry a mutation, which controls cell growth and death, in the cancer-causing gene KRAS. The KRAS oncogene is difficult to target directly with a drug, so researchers are testing workarounds.  One approach targets the AKT and MAP-Kinase (MAPK) downstream signaling pathways that support KRAS.

"Some clinical trials have targeted these pathways, but high toxicity levels and therapeutic resistance development precluded further investigation of these regimens," said Youngkyu Park, one of the investigators. "Toxicity can occur when anti-tumor agents aren't malignancy-specific.”

To develop an effective cancer drug, the research team created drug cocktails that block both the main pathways supporting pancreatic cancer cell growth and cancer cell-specific resistance pathways.

By culturing normal human cells and cancer cells in 3D organoid models and testing them concurrently, the team was able to distinguish particular signaling mechanisms that only affected pancreatic cancer cells. This allowed them to pinpoint the ERBB signaling pathway as the pancreatic cancer-specific resistance mechanism following AKT/MAPK blockade.

By inhibiting ERBB signaling in addition to MAPK signaling, the researchers observed pancreatic tumors shrink in organoid mouse model of PDA.

"We hope this study will help other research groups to use the same methodological approach we use in the paper," said Mariano Ponz-Sarvisé, an author on the study. "I believe that for some drugs, this approach can help find new avenues to overcome resistance."

Source: EurekAlert! Science News, Sept. 9

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