Scientists at Cold Spring Harbor Laboratory (CSHL) say they have found a way to tackle the problem of drug resistance and stop the growth of pancreatic ductal adenocarcinoma (PDA) tumors in mice. Their findings (“Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer”) are published in the journal Clinical Cancer Research.

David Tuveson
David Tuveson, MD, PhD
Roy J. Zuckerberg professor of cancer research, Johns Hopkins University

Pancreatic cancer has a five-year survival rate of only eight percent. David Tuveson, MD, PhD, the Roy J. Zuckerberg professor of cancer research, Johns Hopkins University, and colleagues are focused on identifying better treatment strategies to help prolong survival for patients, including new drugs that can be introduced into clinical trials. 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 drug directly, so researchers are testing indirect routes to shutting it down. One approach targets the AKT and MAP-Kinase (MAPK) downstream signaling pathways that support KRAS.

“KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. Additionally, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities,” the investigators wrote.

“Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor Erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies.

“Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.”

“Some clinical trials have targeted these pathways, but high toxicity levels and therapeutic resistance development precluded further investigation of these regimens,” said Youngkyu Park, PhD, a research investigator in the Tuveson lab. “Toxicity can occur when anti-tumor agents aren’t malignancy-specific. That means they risk killing healthy cells as well.”

The Tuveson lab encountered the problem of resistance pathways when it tried to barricade both the AKT and MAPK pathways in PDA. To develop an effective cancer drug, the 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, MD, PhD, a former CSHL Clinical Fellow and an author on the study. “I believe that for some drugs, this approach can help find new avenues to overcome resistance.”

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