Abstract/Summary: Mutations in KRAS are among the most common aberrations in cancer. Mutant KRAS drives proliferation and survival through canonical RAS-RAF-MEK-ERK-RSK (RAS-RSK) signaling. While KRASG12D, a major mutation found in cancers remains undruggable, a smaller subset of patients carry KRASG12C mutation for which new targeted drugs have emerged. Several KRASG12C inhibitors have been studied in pre- clinical and Phase I/II/III studies and one such inhibitor sotorasib has received FDA approval for KRASG12C mutant NSCLC patients. Despite this success, the objective response rates from sotorasib or other related inhibitors has been modest and durability of response needs to be improved. A number of resistance mechanism have been proposed and strategies to overcome therapy resistance to KRASG12C inhibitors is a topic of intense investigations. We have discovered that proteins in the RAS can influence the nuclear protein transport. In normal cells, the export of nuclear cargoes is mediated by the Karyopherin family protein exportin-1/XPO1 through nuclear export signal sequence recognition and is facilitated by a RAS downstream effector RanGTP. This makes RAN a mediator between growth signaling and nucleocytoplasmic transport that can be activated through classical RAS-RSK pathway. Ran binding protein 3 (RanBP3) is recognized to be phosphorylated through RSK, resulting in the promotion of RanGDP to RanGTP conversion through RCC1 thereby enhancing Ran-dependent nucleocytoplasmic transport (schema). Such over-active nuclear export has been shown to promote therapy resistance through mislocalization dependent inactivation of tumor suppressor proteins. More significantly, our new findings show that specific inhibitors of nuclear export (SINE) compounds can enhance the efficacy of KRASG12C inhibitors. We hypothesize that SINE-KRASG12C inhibitors could become a unique combination for KRASG12C mutant tumors. Additionally, studying this unique combination will also help uncover the tangible link between KRAS and nuclear protein export signaling. Our specific aims are Aim 1. Characterize the synergy between SINE compounds and KRASG12Ci using high throughput strategies. Aim 2. Demonstrate synergy between SINE KRASG12Ci using patient derived xenograft. Impact: Mutant KRAS remains an impenetrable fortress and an unmet clinical need. This work will lead to the advancement of a novel combination that target two highly sought after cancer targets i.e. KRASG12C and XPO1. Additionally, the proposed experiments will also enhance the fundamental understanding of the interaction between mutant KRAS and nuclear protein export pathways and its consequence of therapy resistance. The proposed pre-clinical studies will bring forward a new and personalized therapy for KRASG12C mutant driven resistant tumors.