Cellular targets to overcome KRAS inhibitor resistance in pancreatic tumors identified

A study led by University of Cincinnati Cancer Center researchers sheds new light on how pancreatic cancer cells resist treatment and points to potential new combination therapies to make treatments more effective.

The research, led by corresponding author Andrew Waters, Ph.D., and co-first authors Haley Todd, Grace Goodheart and Szu-Aun Long, MD, was recently published in Cancer Research.

The research focuses on a gene called KRAS, the most frequently mutated oncogene in human cancer, which is mutated in more than 90% of pancreatic cancers and helps drive cancer cell growth.

Waters said the field has made significant progress in the past few years in moving drugs targeting KRAS to clinical trials and toward Food and Drug Administration approval, including his lab’s basic science research and clinical trials now open at the Cancer Center and across the country.

But while early clinical data shows positive results, most patients will ultimately develop drug resistance to KRAS inhibitor treatments—and if that is their sole treatment, the cancer will recur.

“In this study, we sought to identify critical cellular targets that could improve a pancreatic tumor’s sensitivity to KRAS inhibitors,” said Long, a fellow in the Department of Surgery in UC’s College of Medicine and researcher in the Waters lab.

“Through studying KRAS inhibitor mechanisms of resistance, we can identify potential therapeutic combinations for the treatment of pancreatic cancer,” added Todd, a graduate assistant in the Waters lab.

Using KRAS-mutated pancreatic cancer cell lines and CRISPR technology, the team screened for genes that play a role in sensitivity to KRAS-inhibiting drugs.

“We have identified certain patient populations that may preferentially respond to anti-KRAS and anti-EGFR combination therapies,” said Waters, a Cancer Center researcher and assistant professor in the Department of Surgery in UC’s College of Medicine.

EGFR is a critical protein that regulates cell growth and survival and is often overexpressed in various cancers. The team found it also plays a role in pancreatic cancer cells’ resistance to KRAS therapies.

“Our study describes ways that pancreatic cancer cells resist targeted KRAS inhibitor treatment. And while finding resistance mechanisms may seem discouraging, understanding how cells are resilient and adapt leads us one step closer to being able to provide more efficacious and personalized treatments for patients,” said Goodhart, a graduate assistant in Waters’ lab.

Moving forward, the team plans to continue to build on its previous data to learn more about how pancreatic cancer adapts to and resists treatment, including through human-based tissue and biopsy samples. A current trial open at the Cancer Center is testing the combination of a KRAS inhibitor and a EGFR inhibitor in patients with gastrointestinal solid tumors, including metastatic pancreatic cancer.

“This is a true example of a bench to bedside to bench approach,” Waters said. “One thing the field is starting to appreciate is that the cancer cells can hijack or co-opt the functions of the healthy cells to do their bidding.

“And due to generous philanthropic investments in our research—combined with collaborations with translationally minded surgeon-scientists like Dr. Syed Ahmad—we are now beginning to untangle functionally how the cancer cells are doing this.”