Assistant Professor, Translational Molecular Pathology
The University of Texas MD Anderson Cancer Center
Targeting IL-18 driven early survival mechanism to improve KRAS inhibitor therapy in pancreatic cancer
Chen Laboratory at MD Anderson
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Overview
Aim: Treatment and Therapy
The vast majority of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is driven by mutations in the KRAS gene. Recent efforts to target mutant KRAS proteins have resulted in promising initial clinical results. Tumor cells, however, can adapt and often become resistant to KRAS inhibition. Since tumor cells can use multiple mechanisms to survive drug treatment, this resistance is often difficult to treat once established. One potential method to avoid drug resistance, specifically resistance to mutant KRAS inhibitors, is to target the earliest stage of the process by uncovering how a small number of cancer cells (called “persister” cells) escape and survive the initial treatment.
Yang Chen, PhD, an Assistant Professor of Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center, a 2026 Hirshberg Foundation Seed Grant recipient, propose that by understanding the mechanisms of how these “persister” cells survive can result in treatment combinations that potentially stops resistance before it begins. His proposal Targeting IL-18 driven early survival mechanism to improve KRAS inhibitor therapy in pancreatic cancer stems from the discovery by his lab that the expression of interleukin-18 (IL-18) is increased by tumor cells after treatment with KRAS inhibitors and may be a key part of the escape process by “persister” cells. This expression of IL-18 by tumor cells results in the expression of CD47, a protein that acts as a “don’t eat me” signal to scavenger immune cells called macrophages, potentially enabling their survival.
In this study, Dr. Chen’s group will investigate the role of IL-18 in promoting early tumor cell survival during KRAS inhibition and evaluate whether targeting IL-18 increases responses to KRAS inhibitors. By defining how IL-18 drives cancer cell survival and immune evasion during KRAS inhibition, this work has the potential to improve the effectiveness and durability of KRAS-targeted therapies and benefit patients undergoing pancreatic cancer treatments.
Dr. Chen wrote to say, “Thank you so much for your confidence in my research, I am greatly honored and grateful to receive the generous support of the Hirshberg Foundation Seed Grant.”
