ABSTRACT
The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy may not respond and generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitor MRTX1257 in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines MiaPaCa-2 and NCI-H2122 in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. A combination of selinexor with KRAS G12C inhibitors potentiated the inhibition of KRAS expression in MiaPaCa-2 cells. NF-kB protein expression was also markedly reduced by selinexor and MRTX1257 combination. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models.
Significance In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.
Competing Interest Statement
ASA received funding from Karyopharm, EISAI, Jannsen, and Rhizen. ASA received speaker fees from Karyopharm Therapeutics Inc. ASA is a council member at GLG and Guidepoint. HM received an honorarium from AztraZeneca and has an advisory role in Zentalis. DU is on the advisory board of Daiichi Sankyo and AstraZeneca.
Footnotes
Funding: Work in the lab of Azmi AS is supported by NIH R37 grant R37CA215427. The authors thank the SKY Foundation, and Perri Family Foundation for supporting part of this study.
Conflict of interest statement: ASA received funding from Karyopharm, EISAI, Jannsen and Rhizen. ASA received speaker fees from Karyopharm Therapeutics Inc. ASA is a council member at GLG and Guidepoint. HM received honorarium from AztraZeneca and has advisory role in Zentalis. DU is on the advisory board of Daiichi Sankyo and AstraZeneca.