WCLC 2025 - Posters & ePosters-P3.03.01 Rb Inactivation as a Hallmark of Squamous Transformation in EGFR-Mutant Lung Cancers

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This study from Memorial Sloan Kettering Cancer Center investigates the role of Rb (retinoblastoma) pathway inactivation in squamous transformation of EGFR-mutant lung cancers, a known resistance mechanism to osimertinib that occurs in up to 8% of patients. Squamous-transformed tumors have poorer outcomes compared to adenocarcinoma histology when treated with first-line osimertinib.<br /><br />The research involved clinical analysis of EGFR-mutant patients on osimertinib and multi-omic profiling (genomic, transcriptomic, proteomic) of tumors before and after squamous transformation, including microdissected adenosquamous components and genetically-engineered xenograft models treated with osimertinib.<br /><br />Key findings include:<br /><br />1. Enrichment of Rb and AKT pathway mutations in tumors undergoing squamous transformation, associated with shorter time to treatment discontinuation and worse overall survival.<br /><br />2. Evidence of Rb pathway inactivation in transforming tumors demonstrated through genomic alterations, transcriptional signatures (notably E2F target gene upregulation), and proteomic data.<br /><br />3. Experimental genetic deletion of Rb in EGFR-mutant xenografts induced squamous-like phenotypes at the single-cell level, confirming Rb loss as a driver of histologic transformation.<br /><br />4. Combined alterations in Rb (RB1) and AKT/mTOR pathways correlate with resistance to osimertinib therapy and poorer clinical outcomes.<br /><br />The study highlights that detection of Rb pathway mutations could serve as a biomarker for identifying patients at high risk for squamous transformation and consequently poor response to EGFR-targeted therapies. These findings underscore Rb inactivation as a hallmark of squamous transformation and reveal potential molecular targets for overcoming resistance in EGFR-mutant lung cancers.

Asset Subtitle

Mark Jeng

Meta Tag

Speaker Mark Jeng

Topic Tumor Biology – Translational Biology

Keywords

Rb pathway inactivation

squamous transformation

EGFR-mutant lung cancer

osimertinib resistance

adenosquamous carcinoma

multi-omic profiling

AKT/mTOR pathway mutations

genetically-engineered xenograft models

E2F target gene upregulation

biomarkers for resistance