2025 Targeted Therapies of Lung Cancer (TTLC) - Posters-PP01.36 Clinicogenomic Analysis of EGFR-mutant Lung Cancers Identifies Rb and AKT Pathway Alterations as Hallmarks of Squamous Transformation

PP01.36 Clinicogenomic Analysis of EGFR-mutant Lung Cancers Identifies Rb and AKT Pathway Alterations as Hallmarks of Squamous Transformation

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The document outlines research on the resistance mechanism in EGFR-mutant lung adenocarcinoma (LUAD), highlighting histologic transformation into squamous carcinoma (LUSC) in about 5-8% of patients treated with osimertinib. This transformation correlates with poorer clinical outcomes, and the underlying molecular mechanisms are not well understood.<br /><br />The study, conducted by researchers from the Memorial Sloan Kettering Cancer Center, aims to pinpoint genomic drivers of this transformation and evaluate clinical outcomes in patients with high-risk genomic profiles using xenograft models. The research involves genomic characterization of EGFR-mutant tumors undergoing LUSC transformation, utilizing pre- and post-transformation specimens, and microdissected components from lung adenosquamous tumors.<br /><br />Key findings include the enrichment of mutations in the Rb and AKT pathways in transforming EGFR-mutant lung cancers. Patients with these mutations experience worse clinical outcomes when on frontline osimertinib therapy. The study particularly notes that Rb inactivation is a significant promoter of LUSC transformation in xenograft models, suggesting these mutations could serve as indicators for high-risk patients prone to treatment resistance and histological transformation.<br /><br />Methods involved examining both clinical outcomes of EGFR-mutant LUAD patients who underwent the MSK-IMPACT and employing EGFR-mutant xenograft models to replicate squamous transformation under osimertinib treatment.<br /><br />The findings suggest potential pathways for future research and targeted therapies, emphasizing the importance of genetic testing for Rb and AKT pathway mutations in predicting patient outcomes and tailoring treatment strategies. Researchers underscore the role of these pathways as hallmarks of resistance in osimertinib treatments, with the aim to improve management and therapeutic interventions for high-risk EGFR-mutant lung cancer patients.

Asset Subtitle

Mark Jeng

Keywords

EGFR-mutant lung adenocarcinoma

osimertinib resistance

histologic transformation

squamous carcinoma

genomic drivers

Rb pathway mutations

AKT pathway mutations

xenograft models

MSK-IMPACT

targeted therapies