Targeting Acquired Resistance to KRAS Inhibitors in Pancreatic Cancer
Abstract
Almost all pancreatic cancers contain mutations of the KRAS gene. Our previous study and others have demonstrated that mutant KRAS is required for tumor initiation and continued tumor growth, substantiating the therapeutic potential of targeting KRAS in pancreatic cancer. However, attempts to target mutant KRAS had been unsuccessful for the past 4 decades and the mutant KRAS had long been deemed undruggable until most recently. The heroic effort in the research of targeted therapies for mutant KRAS has led to the development of first-in-class KRAS inhibitors targeting KRAS mutation, representing a symbolic end to the myth of KRAS un-druggability and providing an unprecedented opportunity for treating cancer patients with mutant KRAS. While KRAS inhibitor targeting the common KRAS mutation of lung cancer and colon cancer has been recently approved by the U.S. Food and Drug Administration (FDA), KRAS inhibitors specific for mutations commonly found in pancreatic cancer are expected to enter clinical trial later this year. Unfortunately, based on the current clinical data from lung cancer and colon cancer patients, although targeting KRAS-mutated tumors with KRAS inhibitors shows encouraging response in patients, the majority of tumors that initially respond to KRAS inhibition quickly develop resistant disease, which severely limits the survival benefit of KRAS inhibitors. Understanding and targeting the underlying resistant mechanisms thus becomes the major challenge to improve the clinical outcome of KRAS-targeted therapy. To tackle this urgent problem, this application will capitalize on the PI s track record and expertise in the area of KRAS signaling and biology and propose a comprehensive research program focusing on understanding and targeting the mechanisms of acquired resistance to KRAS targeted therapy. Our pioneer work of using a novel genetically engineered preclinical mouse model of pancreatic cancer has predicted the resistance to KRAS targeted therapy and identified the activation of YAP1 gene as the potential driver for acquired resistance. Our ongoing studies further demonstrate that YAP1 activity is significantly upregulated in subset of tumor cells that can survive KRAS inhibition. Deletion of YAP1 eliminates these cells and abolishes the capacity of tumor cells to develop resistance to KRAS inhibition. In line with such a notion, ablation of YAP1 with therapeutic agents currently under clinical trial in solid tumors significantly sensitized patient-derived tumor models to KRAS inhibitor treatment, underscoring the potential of targeting YAP1 to overcome resistance to KRAS targeted therapy. Thus, the overall objective of our proposed study is to understand how YAP1 functions in tumors resistant to KRAS inhibitors, and whether targeting YAP1 is effective for achieving sustainable therapeutic responses. Our proposed study is tailored to provide answers to the outstanding questions about how KRAS mutated pancreatic cancers evolve to become resistant to KRAS inhibitors, how adaptable KRAS mutant pancreatic cancers are to perturbations of the resistant machinery, and whether targeting such a resistant mechanism may potentially cooperate with the KRAS inhibitor to eradicate KRAS mutant pancreatic cancer. Our proposed studies are aligned with the FY22 PCARP Focus Area of targeting cancer sensitivity and resistance mechanism. Both novel mouse models and highly sensitive single-cell sequencing technologies, as well as new, clinically ready therapeutic agents will be adopted to ensure the success of the proposal. The concept of targeting YAP1 to overcome resistance to KRAS inhibitors is another major innovation of the study. In the short term, an outcome of the proposed study would offer important mechanistic insights into how pancreatic cancer evolves to become resistant to KRAS-targeted therapy and provide much-needed evidence as to how these tumors may be targeted in clinical trials. In
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311082
Entities
People
- Haoqiang Ying
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army