314P - Let’s bring back old drugs to conquer resistance to KRAS G12C inhibitors in NSCLC

Background

Once considered undruggable, mutant KRAS has recently emerged as a promising target for anticancer therapies. KRASG12C is the most common mutant isoform in NSCLCs, accounting for 41–49% of cases with G12 substitutions. In KRAS-mutant lung adenocarcinomas that have received previous anticancer therapies, treatment with a selective KRAS G12C inhibitor (sotorasib) causes partial responses in around 38 % of patients. Despite the significant therapeutic responses associated with KRAS inhibitors, their efficacy in patients has been short-lived due to the emergence of drug resistance.

Methods

We're concentrating on combining KRAS inhibition with drugs that target proteins upstream of KRAS to help overcome resistance to KRAS inhibitors to improve their effectiveness and longevity. Cotargeting upstream may be more effective since it provides more robust MAPK pathway suppression as well as prevent reciprocal activation of parallel prooncogenic signalling pathways. A combination of protein tyrosine phosphatase SHP2 inhibitor with the inhibitor targeting ErbB receptor tyrosine kinases can prove to be an effective approach for overcoming lung cancer resistance to KRAS inhibitors. What makes our concept different is that the inhibitors are identified based on a drug repurposing approach. We carried out in silico virtual screening of the FDA approved drugs followed by MD simulations to filter the drugs. Anticancer in vitro assays and isoform-specific pulldown assays were carried out on the top lead compounds in combinations. These mechanisms were then observed in transgenic zebrafish to confirm the anti-lung cancer potential of the repurposed drugs. The impact of drugs on tumor growth were evaluated through the comparison of tumor mass and dispersion of cells.

Results

Using these approaches we have identified antipsychotic drugs to have high binding affinity (-9 to -12 Kcal/mol) with the upstream mutated proteins of MAPK pathway when compared to the standard inhibitors which are proved to have several side effects. Two of the drugs have shown considerably good cytotoxicity against A549 cells.

Conclusions

Cotreatment of cells with a SHP2 inhibitor, resulted in more persistent ERK suppression by preventing RTK-mediated MAPK pathway reactivation.

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.