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.

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.

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