2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.09: Integrin-Linked Kinase Drives Drug-Tolerant Persister Cell Survival and EMT in Response to EGFR Inhibition in Lung Adenocarcinoma

PP01.09: Integrin-Linked Kinase Drives Drug-Tolerant Persister Cell Survival and EMT in Response to EGFR Inhibition in Lung Adenocarcinoma

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The study by Amack et al. investigates the role of Integrin-linked kinase (ILK) in mediating drug tolerance and epithelial-mesenchymal transition (EMT) in response to epidermal growth factor receptor (EGFR) inhibitor treatment in lung adenocarcinoma (LUAD). Lung cancer is a leading cause of cancer mortality, and resistance to EGFR tyrosine kinase inhibitors (TKIs) presents significant challenges for treatment. Current understanding suggests that EMT is a non-genetic mechanism contributing to EGFR TKI resistance, often associated with poorer outcomes in patients.<br /><br />ILK, a protein known to promote EMT across various cancers, is tied to poor prognosis in LUAD patients managed with EGFR TKIs. The authors hypothesize that ILK supports the survival of drug-tolerant persister (DTP) cells and encourages EMT in response to EGFR inhibition. Their findings reveal that high ILK expression correlates with an EMT signature in EGFR mutant LUAD patients and cell lines. Specifically, in EGFR mutant HCC4006 cells that developed resistance to Osimertinib (an EGFR TKI), EMT characteristics were evident, and DTP states were sustained.<br /><br />RNA sequencing of these resistant cells unveiled significant gene expression alterations, highlighting biological processes influenced by ILK. Knocking down ILK was shown to enhance susceptibility to Osimertinib, indicating its role in maintaining DTP viability and EMT progression toward drug resistance. Further mechanistic studies revealed that ILK may exert its protective effects in part through YAP (Yes-associated protein) activity and mesenchymal reprogramming.<br /><br />Addition of extracellular matrix (ECM) further emphasized ILK's cytoprotective effects, suggesting potentials for therapeutic interventions. Notably, the pharmacological inhibition of ILK in combination with Osimertinib significantly decreased DTP cell viability, presenting a promising strategy to improve treatment outcomes in LUAD. These observations underscore ILK's integral involvement in resistance pathways and propose pathways to potentially overcome TKI resistance in lung adenocarcinoma.

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Rocky Shi

Keywords

Integrin-linked kinase

epithelial-mesenchymal transition

EGFR inhibitor

lung adenocarcinoma

drug resistance

Osimertinib

drug-tolerant persister cells

YAP activity

extracellular matrix

therapeutic interventions