Preclinical studies of KRAS and EGFR mutations in lung cancer PDXs

项目总结/文摘

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-039. Lung cancer is the leading cause of cancer incidence and mortality in all Americans but disproportionally high in communities of color. Compared to Whites, for example, African Americans and Latinos are 18% and 16% less likely to have an early lung cancer diagnosis, respectively. The 5-year survival of African Americans and Latinos is also 21% and 16% lower than White patients. However, the incidence and mortality rates in US minority populations are closely linked to their smoking rates. In African American and some Asian/Pacific Islander groups such as Hawaiian and Samoan, lung cancer is the top cause of cancer mortality. Lung cancer disproportionally affects African American men, who have incidence and mortality rates of 15% and 18% higher than White men. Even in Latinos, the ethnic group with the lowest smoking rates in the nation, lung cancer remains the first cause of cancer mortality in men. EGFR and KRAS are the most common mutations in lung tumors and are strongly associated with race, smoking, and genetic ancestry. KRAS is commonly diagnosed in Whites and African Americans, in men and smokers/former smokers. Asians and Latinos, on the other hand, have a significantly lower frequency of KRAS mutations but are enriched with mutations in EGFR. EGFR mutations in Asian and Latino patients are prevalent in never smoker women. Until recently, most of the targeted therapies for lung cancer were developed for EGFR mutant tumors, while KRAS was considered “undruggable.” This, however, changed in the last 12 months with the FDA approval of sotorasib, a molecule that increases overall response rate and progression-free survival in tumors carrying the KRAS G12C mutation. Despite these important advances, a significant fraction of patients either lack response or develop resistance to EGFR and KRAS targeted therapies. In this supplement, we are leveraging the resources of our minority PDX (MPDX) center to investigate mechanisms associated with response to inhibitors for KRAS and EGFR in models from White and minority patients. Our Specific Aims are as follows: Aim 1. To determine the activity of direct KRAS G12C inhibition of sotorasib in the presence or absence of dual inhibition of glycolysis and glutaminolysis with sapanisertib and telaglenastat (CB839) in KRAS G12C mutant PDXs with clinically relevant co-alterations (p53/Keap1). Aim 2. To carry out a feasibility study for identifying biomarkers associated with EGFR inhibitor resistance in lung PDXs from Asian and White patients. This project will increase our understanding of responses to targeted therapies for lunch cancer and serve as a springboard for future clinical trials on precision medicine in white and minority patients.