KRAS Inhibitor Treatment Disparities in Non-Small Cell Lung Cancer Patients: Increasing Equity Through Precision Medicine
Avrosina Kamel1,4 Frank McCormick2,3, Andrew L. Wolfe4,5,6.
1Macaulay Honors College and Human Biology Program, Hunter College, New York, NY.
2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
3National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD.
4Department of Biological Sciences, Hunter College, City University of New York, New York, NY.
5Department of Pharmacology, Weill Cornell Medicine, New York, NY.
6Biochemistry Ph.D. Program and Molecular, Cell, and Developmental Biology Ph.D. Subprogram, City University of New York Graduate Center, New York, NY.
KRAS is a proto-oncogenic GTPase that normally activates pathways involved in cell growth, differentiation, and survival. KRAS is mutated in about 25% of all cancers and 33% of lung cancer. A first-in-class KRAS G12C inhibitor approved in 2021, sotorasib, is dependent on mutant cysteine at the 12th codon for its inhibitory function. Most patients relapsed after ~6 months, indicating development of resistance mechanisms. Therefore, we sought to identify synthetic lethal drug combinations to eliminate possible rerouting mechanisms of KRAS activity. A combinatorial drug screen identified GSK3β as a possible candidate for this interaction. We tested two GSK3β inhibitors – Kenpaullone and SAR502250 – in a combination drug experiment with sotorasib; however, the results were not indicative of synergy. Several possible effector pathways linked KRAS and GSK3β. Immunoblots to test proposed pathway interactions identified changes in inhibitory phosphorylation of GSK3β induced by SAR502250. Disparity trends exist in the population prevalence of the targetable KRAS allele, recruitment in clinical trials, and objective response rates (ORR). G12C mutations were more prevalent in White populations than in Black or Asian populations. In the Phase I/II clinical trials for sotorasib, 102 White, 18 Asian, and 2 Black patients were recruited. The drug’s ORR was 18% in Asian populations, 40% in White populations, and 0% in Black populations, indicating a clear treatment disparity. Understanding why some populations tend to display enhanced drug resistance is critical to increasing equity in cancer therapy, emphasizing the need to expand treatment modalities.
