2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.22: Targeting GTP-Bound KRAS and mTOR in Lung Adenocarcinoma and Squamous Cell Carcinoma Harboring KRAS G12C

PP01.22: Targeting GTP-Bound KRAS and mTOR in Lung Adenocarcinoma and Squamous Cell Carcinoma Harboring KRAS G12C

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The study explores the efficacy of combined therapy targeting KRAS G12C and mTOR in lung adenocarcinoma and squamous cell carcinoma. KRAS mutations, particularly G12C, are common in these cancers, making targeted inhibitors crucial. Previous studies have focused on the potential of combination therapies for KRAS mutant cases. This study investigates the effects of KRAS G12C inhibitors alongside mTOR inhibition in three lung cancer cell lines, including two adenocarcinoma and one squamous cell carcinoma.<br /><br />Three KRAS G12C inhibitors (AMG 510, MRTX849, and ARS-1620) were tested, and the increase in mTOR expression following treatment was noted. The study utilized RNA sequencing to assess genetic changes post-treatment and found significant mTOR upregulation across all tested cell lines.<br /><br />Combination therapy involving each KRAS G12C inhibitor with an mTOR inhibitor (RAD001) consistently demonstrated synergistic effects in MTS and clonogenic assays, indicating increased efficacy. This synergy suggests the potential to effectively inhibit key cancer growth pathways, specifically the RAS-MEK-ERK and PI3K-AKT-mTOR pathways. Notably, this combination therapy abrogated the activation of GTP-bound KRAS, pmTOR, and pERK, pointing to its potential utility in overcoming resistance pathways associated with KRAS-driving lung cancer.<br /><br />The researchers conclude that a combined approach targeting KRAS G12C and mTOR holds promise for treating primary lung cancers with these mutations, potentially benefiting both adenocarcinoma and squamous cell carcinoma types with KRAS G12C mutations. This synergy may offer a new therapeutic pathway, especially for cases where monotherapy has limited efficacy due to alternative genetic pathway activations.

Asset Subtitle

Masaoki Ito

Keywords

KRAS G12C

mTOR

lung adenocarcinoma

squamous cell carcinoma

combination therapy

KRAS inhibitors

mTOR inhibition

synergistic effects

cancer growth pathways

resistance pathways