Exploring Metabolic Vulnerability of KRAS G12C Inhibitor Resistance Using a Microfluidic Multiarray Platform
Abstract
In 2022, in the U.S., 236,740 new cases of lung cancer patients are estimated to be diagnosed. The United States military population has greater exposure to hazardous chemicals and cigarette smoking. These factors lead to a remarkably higher incidence of lung cancer compared to the civilian population. Although great advances have been made, lung cancer has a poor prognosis because it is often diagnosed at advanced stages when patients cannot benefit from surgery and rely on traditional chemotherapy or targeted therapies if possible. Although KRAS is the most frequent gene mutated in lung adenocarcinoma, traditional chemotherapy has been the primary treatment for NSCLC patients with KRAS mutations. Chemotherapy has only shown promise when combined with immune checkpoint inhibitors, but it does not benefit all patients. Until recently, targeted therapies against KRAS have not been successful, but specific inhibitors of the most frequent KRAS mutation, G12C, have shown promising results in vitro and in clinical trials leading to the FDA approval of sotorasib. Nevertheless, de novo or acquired drug resistance to these types of inhibitors have already been shown; therefore, it is crucial to identify the mechanisms underlying drug resistance, and to develop methods to overcome this issue. Tumor cells try to evade drug treatment pressure with the activation of countless different mechanisms; thus, resistant cells show a completely different phenotype. All the alterations derived from the acquisition of drug resistance rely on changes in the epigenome to activate or deactivate certain genes. Some of these adaptations that tumor cells engage to survive create additional vulnerabilities that can be targeted pharmacologically, providing new treatment strategies to overcome drug resistance. This proposal aims to understand the changes occurring during acquired G12Ci drug resistance in order to design new therapeutic approaches. We have found a strong correlation between G12C inhibitors’ resistance and NNMT and its nuclear localization, an essential enzyme that can modulate the whole epigenetic landscape affecting a myriad of cellular processes. The result of this proposal is to describe unknown mechanisms of drug resistance and provide an alternative therapeutic approach for the U.S. Veterans that are not responsive to this drug treatment. This two-year study will validate that NNMT inhibition in KRAS G12C resistant tumors is a realistic and promising therapeutic treatment that will benefit Veterans. This proposal addresses three FY22 LCRP Areas of Emphasis by understanding mechanisms of resistance to treatment, developing predictive markers and identifying innovative treatment strategies that will benefit the military population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310486
Entities
People
- Takeshi Shimamura
Organizations
- United States Army
- University of Illinois at Chicago