Abstract C028: Effects of co-treatment with polyisoprenylated cysteinyl amide inhibitors and sotorasib on cell viability and ras signaling pathways in an African American lung cancer cell line

Abstract Lung adenocarcinoma (LUAD) is the most prevalent type of lung cancer among Blacks/African Americans(B/AAs) and all other racial and ethnic groups. Therapies that directly target mutant KRAS, the most common driver of LUAD, have been difficult to develop. Anti-cancer drugs such as Sotorasib, a KRASG12C inhibitor, were developed to treat cancers driven by the mutant KRAS protein. Nevertheless, recent studies have highlighted the limitations of Sotorasib as a viable long-term treatment due to intrinsic changes in cells, resulting in resistance and relapse. Polyisoprenylated Cysteinyl Amide Inhibitors (PCAIs) are novel anti-cancer agents developed to target hyperactive G-proteins such as KRAS, RHOA, CDC42 and RAC1 by disrupting their polyisoprenylation-dependent interactions. Previous work, using lung adenocarcinoma cell lines NCI-H23, derived from a B/AA male patient, revealed that PCAIs induce apoptosis in cells while inhibiting cell migration and invasion by 82%. Furthermore, the PCAI treatment induced hyperphosphorylation of the MAP kinase proteins MEK1/2, ERK1/2, p90RSK and AKT in the PI3K/AKT pathway. Current experiments seek to explore the effects of co-treatment with PCAIs and Sotorasib on cell viability and phosphorylation of MAP kinase proteins. Cell viability studies indicate increased potency when cells are co-treated with PCAIs and Sotorasib compared to treatments with individual compounds. The EC50 obtained for individual treatments of PCAI NSL-AB-51 and Sotorasib were 2.7 mM and 19 mM, respectively. The EC50 obtained for the treatments with varying concentrations of NSL-AB-51 combined with 18 mM Sotorasib, and varying concentrations of Sotorasib combined with 2.7 mM NSL-AB-51 were 1.8 mM and 10 mM, respectively. Preliminary western blot data indicates that the PCAIs induce the hyperphosphorylation of the MAP kinase pathway kinases MEK1/2, ERK1/2, and p90RSK. However, introduction of Sotorasib reverses the PCAI-induced hyperphosphorylation. Ongoing work is aimed at elucidating the interplay between PCAIs and Sotorasib with respect to cell viability and growth signaling pathway activations using cell lines with different KRAS mutations. Citation Format: Justin K. Mensah-Mamfo, Kweku Ofosu-Asante. Effects of co-treatment with polyisoprenylated cysteinyl amide inhibitors and sotorasib on cell viability and ras signaling pathways in an African American lung cancer cell line [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C028.