2022 World Conference on Lung Cancer (ePosters)-EP16.03-012. Novel Human-derived EML4-ALK Fusion cell lines identify ribonucleotide reductase RRM2 as a Target of Activated ALK in NSCLC

EP16.03-012. Novel Human-derived EML4-ALK Fusion cell lines identify ribonucleotide reductase RRM2 as a Target of Activated ALK in NSCLC

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This document is a summary of a study that characterizes four novel EML4-ALK-positive non-small-cell-lung-cancer (NSCLC) cell lines. The fusion between EML4 and ALK is responsible for the development of 5-8% of NSCLC cases. The expression of the fusion protein is regulated by EML4, which is involved in microtubule stability, while ALK is a receptor tyrosine kinase.<br /><br />The study investigates the sensitivity of the EML4-ALK cell lines to ALK tyrosine kinase inhibitors (TKIs). The cell lines were treated with alectinib, brigatinib, or lorlatinib, and sequencing confirmed the presence of the EML4-ALK fusions. Genomic analysis identified rare variants in genes, including TP53 mutations and CDKN2A/B deletions. Differential responses to the TKIs were observed among the cell lines.<br /><br />RNA-seq analysis showed the downregulation of E2F targets upon ALK inhibition, indicating the effect of the TKIs on the transcriptional level. Different EML4-ALK fusion variants are expressed in NSCLC, and inhibitors have been developed to target ALK activity. The availability of EML4-ALK NSCLC cell lines allows for a better understanding of the differential responses seen in patients with different EML4-ALK variants.<br /><br />The study also identified the ribonucleotide reductase RRM2 as a downstream target of activated ALK in NSCLC. Pharmacological inhibition of RRM2 alone or in combination with lorlatinib affected cell viability, indicating its potential as a therapeutic target in EML4-ALK-positive NSCLC.<br /><br />Overall, the study provides valuable insights into the genomic heterogeneity and differential responses to ALK TKI treatment in EML4-ALK-positive NSCLC cell lines. The characterization of these cell lines will contribute to the understanding of clinical observations and the development of targeted therapies for NSCLC patients.

Asset Subtitle

Ganesh Umapathy

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Speaker Ganesh Umapathy

Topic Tumour Biology and Biomarkers - Molecular Profiling and Targeted Therapies

Keywords

EML4-ALK-positive

non-small-cell-lung-cancer

NSCLC

cell lines

fusion protein

ALK tyrosine kinase inhibitors

TP53 mutations

CDKN2A/B deletions

RNA-seq analysis

therapeutic target