# Antitumor effects of LPM5140276 and its potential combination with SHP2 inhibition in KRASG12D-mutant cancer

## TL;DR

A new drug, LPM5140276, effectively targets a common cancer mutation and works better when combined with another drug.

## Contribution

LPM5140276 is introduced as a potent KRASG12D inhibitor with a novel binding mechanism and synergy with SHP2 inhibition.

## Key findings

- LPM5140276 binds strongly to KRASG12D and inhibits cancer cell growth.
- Combining LPM5140276 with SHP2 inhibition enhances antitumor effects and overcomes resistance.
- The drug induces cell-cycle arrest and apoptosis in KRASG12D-mutant cells.

## Abstract

KRASG12D is a predominant mutation in pancreatic and colorectal cancers whose targeting has remained a therapeutic challenge. In this study, we introduced LPM5140276 as a potent KRASG12D inhibitor that forms a salt bridge with the Asp12 residue; furthermore, we evaluated its antitumor efficacy, action mechanism, and synergy with the SHP2 inhibitor RMC4550. LPM5140276 was observed to bind to GDP-loaded KRASG12D with high affinity, exhibiting a dissociation constant (KD) of 3.1 × 10−3 nM and an IC50 of 0.5 nM, which was superior to its binding to GTP-loaded KRASG12D. In KRASG12D-mutant cells, LPM5140276 significantly inhibited cell viability by suppressing ERK and AKT phosphorylation to induce G0/G1 cell-cycle arrest and promote apoptosis, which contributed to its antitumor effect in vivo. However, rebound phosphorylation of ERK/AKT and increased SHP2 phosphorylation following the treatment suggested the emergence of bypass resistance. Notably, the combination of LPM5140276 and RMC4550 synergistically suppressed ERK and SHP2 phosphorylation, enhanced G0/G1 arrest and apoptosis, and improved the antitumor efficacy. Thus, LPM5140276 is a promising KRASG12D inhibitor, whose combination with SHP2 inhibition represents a viable strategy for overcoming resistance.