Developing SHP2-based combination therapy for KRAS-amplified cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Gastroesophageal adenocarcinomas (GEAs) frequently exhibit KRAS amplification, leading to high WT KRAS protein levels.
• SHP2 phosphatase promotes KRAS and MAPK pathway activation, making it a potential therapeutic target in GEA.
• Previous studies showed SHP2 inhibition combined with MEK inhibition is effective in GEA.

Purpose of the Study:

• To identify novel combination strategies to enhance SHP2 inhibitor efficacy in KRAS-amplified GEA.
• To explore targets both within and outside the MAPK pathway for combination therapy.
• To evaluate the therapeutic potential of combining SHP2 inhibition with other targeted agents.

Main Methods:

• Genome-wide CRISPR screens were performed in KRAS-amplified GEA cell lines with and without SHP2 inhibition.
• In vitro and in vivo experiments assessed the efficacy of various combination therapies.
• Comparative analysis of combination efficacy in KRAS-amplified versus KRAS-mutant tumors was conducted.

Main Results:

• Candidate targets within the MAPK pathway and upstream receptor tyrosine kinases (RTKs) were identified to enhance SHP2 efficacy.
• Pan-ERBB kinase inhibition showed potent cytotoxicity in vitro and in vivo.
• CDK4/6 inhibition combined effectively with SHP2 inhibition, particularly in KRAS-amplified GEA.

Conclusions:

• SHP2 inhibitors can serve as a foundation for novel combination therapies in KRAS-amplified GEA.
• Combination strategies involving SHP2 inhibition with pan-ERBB kinase or CDK4/6 inhibitors warrant clinical investigation.
• These findings offer promising therapeutic avenues for patients with KRAS-amplified GEA.