2325P - Selinexor (XPO1 inhibitor) in combination with tepotinib (MET inhibitor) potentially inhibits SHOC2 and KRAS G12C in KRAS G12C mutant non-small cell lung cancer

Background

In KRAS-mutant NSCLC cells, SHOC2:MRAS:PP1C complex boosted RAS GTP loading and MAPK pathway reactivation after initial MEK suppression. Nuclear export protein exportin 1 (XPO1) is dependent on KRAS-mutant NSCLC cells, making XPO1 a druggable vulnerability. MET and SHOC2 are required for spheroid growth in KRAS-mutant NSCLC cell lines. Using structure-based drug design (SBDD), we looked at whether selinexor and tepotinib could bind into the 1) KRAS G12C His-95 groove like sotorasib (KRAS G12C inhibitor); 2) SHOC2 phosphatase complex in comparison with celestrol (SHOC2 inhibitor).

Methods

We carried out an in silico molecular docking approach with KRAS G12C and the SHOC2 complex against selinexor and tepotinib using SBDD to determine the binding affinity, intermolecular interactions, and ligand structure complementarity. Sotorasib-resistant H358 and parental H358 KRAS G12C NSCLC cells were examined. In vitro growth inhibitory assays determined cell viability after 3-day treatment. Western blot analyses were performed.

Results

The molecular docking results are summarized in the table. Selinexor and tepotinib interacted with all the three proteins of the complex, unlike celestrol interacting with SHOC2 and MRAS. Within the His-95 groove of KRAS G12C, selinexor forms an H bond and tepotinib forms a pi-sulphur and an H bond with the mutant cys12 residue. Selinexor in combination with tepotinib and omeprazole (v-ATPase inhibitor) has been analyzed. Signaling pathway analysis to demonstrate the SHOC2 and KRAS G12C inhibition is ongoing.

Conclusions

In silico modeling predicts that selinexor and tepotinib have more interactions and better binding affinity with the target proteins when compared to the standard inhibitors. In vitro data will be presented on the validation of selinexor and tepotinib for repositioning in KRAS G12C NSCLC. Table: 2325P

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.