Overcoming resistance in pancreatic cancer treatment

Researchers at Cold Spring Harbor Laboratory (CSHL), US have found a way to tackle the problem of cancer cells developing resistance to drugs and stop the growth of pancreatic tumours in mice. 

Professor David Tuveson’s lab at CSHL is focused on identifying better treatment strategies to help prolong survival for patients with pancreatic cancer, including new drugs that can be introduced into clinical trials.

More than 90 percent of pancreatic cancer patients carry a mutation 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 signalling pathways that support KRAS.

Hematoxylin and Eosin (H&E) and Masson’s Trichrome staining of tumours in organoid mouse model of PDA (credit: Tuveson lab/CSHL, 2019).

“Some clinical trials have targeted these pathways, but high toxicity levels and therapeutic resistance development precluded further investigation of these regimens,” said Youngkyu Park, a Research Investigator in the Tuveson lab. “Toxicity can occur when anti-tumour 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 the AKT and MAPK pathways in PDA. So, to develop an effective cancer drug, they 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 three-dimensional (3D) organoid models and testing them concurrently, the team was able to distinguish particular signalling mechanisms that only affected pancreatic cancer cells. This allowed them to pinpoint the ERBB signalling pathway as the pancreatic cancer-specific resistance mechanism following AKT/MAPK blockade.

By inhibiting ERBB signalling in addition to MAPK signalling, the researchers observed pancreatic tumours shrink in organoid mouse model of pancreatic ductal adenocarcinoma (PDA).

The findings of the study were published in Clinical Cancer Research.