Metabolic Vulnerabilities Associated to G12C Inhibitor Resistance
Abstract
In 2021 in the U.S., 235,760 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, relevant risk factors that lead to a remarkably higher incidence of lung cancer compared to the civilian population. Lung cancer has poor prognosis because 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 mutation. 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 this type of inhibitors are anticipated. Therefore, it is crucial to identify the mechanisms underlying drug resistance and to develop methods to overcome this issue. Tumor cells alter their metabolism to meet their energetic needs and to adapt to environmental changes and, thus, targeting metabolic processes may have advantages over other therapeutic approaches. The limited tolerance of cancer cells for metabolic imbalance creates a vulnerability that can be exploited pharmacologically. These therapies offer heightened specificity since tumor cells seem to be more sensitive to metabolic inhibitors than the normal counterparts reducing drug toxicity. This proposal aims exploit therapeutically these metabolic adaptations selecting a subgroup of patients that could benefit from this type of approach. We have found a strong correlation between G12C inhibitors resistance and NNMT, an essential metabolic enzyme involved in several pathways that renders the cells exceptionally vulnerable to energetic inhibitors. The result of this proposal is not only to describe unknown mechanisms of drug resistance, but also to provide an alternative therapeutic approach for U.S. Veterans who are not responsive to this drug treatment. This 1-year study will validate that metabolic inhibition in KRAS G12C-resistant tumors is a realistic and promising therapeutic treatment that will benefit the Veterans. Therefore, this proposal addresses three FY21 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
- Dec 28, 2022
- Source ID
- W81XWH2210023
Entities
People
- Ines Pulido
Organizations
- United States Army
- University of Illinois at Chicago