Inhibitor of the Nuclear Transport Protein XPO1 Enhances the Anticancer Efficacy of KRAS G12C Inhibitors in Preclinical Models of KRAS G12C–Mutant Cancers

Abstract

The identification of molecules that can bind covalently to KRAS G12C colonies formed by G12C-mutant cancer cells. Mechanistically, the com- and lock it in an inactive GDP-bound conformation has opened the door bination of selinexor with KRAS G12C inhibitors suppressed cell growth to targeting KRAS G12C selectively. These agents have shown promise in signaling and downregulated the expression of cell-cycle markers, KRAS preclinical tumor models and clinical trials. FDA has recently granted ap- and NF-κB as well as increased nuclear accumulation of tumor suppressor proval to sotorasib for KRAS G12C–mutated non–small cell lung cancer protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral ad-(NSCLC). However, patients receiving these agents as monotherapy gener- ministration of a combination of selinexor and sotorasib was demonstrated ally develop drug resistance over time. This necessitates the development to reduce tumor burden and enhance survival. In conclusion, we have of multi-targeted approaches that can potentially sensitize tumors to KRAS shown that the nuclear transport protein XPO1 inhibitor can enhance the inhibitors. We generated KRAS G12C inhibitor–resistant cell lines and ob- anticancer activity of KRAS G12C inhibitors in preclinical cancer models. served that they exhibit sensitivity toward selinexor, a selective inhibitor of Significance:In this study, combining nuclear transport inhibitor selinexor nuclear export protein exportin 1 (XPO1), as a single agent. KRAS G12C with KRAS G12C inhibitors has resulted in potent antitumor effects in preinhibitors in combination with selinexor suppressed the proliferation of clinical cancer models. This can be an effective combination therapy for KRAS G12C–mutant cancer cell lines in a synergistic manner. Moreover, patients with cancer that do not respond or develop resistance to KRAS combined treatment of selinexor with KRAS G12C inhibitors resulted in G12C inhibitor treatment. enhanced spheroid disintegration, reduction in the number and size of