WCLC 2025 - Posters & ePosters-P2.02.15 Drug Tolerance and Persistence to EGFR Inhibitor Treatment Are Mediated by an ILK-SFK-YAP Signaling Axis in Lung Adenocarcinoma

P2.02.15 Drug Tolerance and Persistence to EGFR Inhibitor Treatment Are Mediated by an ILK-SFK-YAP Signaling Axis in Lung Adenocarcinoma

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This study investigates drug tolerance and resistance mechanisms to the EGFR tyrosine kinase inhibitor osimertinib (Osi) in lung adenocarcinoma (LUAD), focusing on the role of integrin-linked kinase (ILK) and YAP signaling. Lung cancer's high mortality is partly due to therapeutic resistance, with epithelial-mesenchymal transition (EMT) and drug-tolerant persister (DTP) cells contributing to treatment failure.<br /><br />Key findings include: HCC4006 Osi-resistant cells show elevated ILK expression associated with EMT and increased nuclear YAP localization, a transcriptional co-activator known to promote survival. ILK knockdown reduces nuclear YAP levels, diminishes DTP survival, and sensitizes cells to Osi treatment in vitro and in vivo, especially under extracellular matrix-rich conditions that typically support resistance. Pharmacological inhibition of ILK synergizes with Osi, reducing colony formation and viability of DTP cells and delaying resistance onset.<br /><br />Analysis of patient data demonstrates high ILK expression correlates with EMT signatures and off-pathway resistance mechanisms in EGFR mutant LUAD, linked to poor prognosis. ILK appears to activate a signaling axis involving Src family kinases (SFK) and YAP that drives DTP survival and EMT reprogramming, enabling cells to survive initial therapy without genetic resistance mutations.<br /><br />The study supports ILK as a key mediator of non-genetic resistance, promoting cytoprotection and mesenchymal transformation during EGFR TKI therapy. Targeting ILK can improve responses to osimertinib by disrupting this survival pathway and preventing or delaying resistance development. These findings propose ILK inhibition combined with EGFR TKIs as a promising therapeutic strategy to overcome drug tolerance and resistance in lung adenocarcinoma patients.

Asset Subtitle

Rocky Shi

Meta Tag

Speaker Rocky Shi

Topic Tumor Biology – Preclinical Biology

Keywords

osimertinib resistance

lung adenocarcinoma

integrin-linked kinase

ILK inhibition

YAP signaling

epithelial-mesenchymal transition

drug-tolerant persister cells

EGFR tyrosine kinase inhibitor

Src family kinases

non-genetic drug resistance