EML4-ALK variant-specific genetic interactions shape lung tumorigenesis
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ABSTRACT:
PROVIDER: PRJNA1284293 | ENA |
REPOSITORIES: ENA
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Project description:Oncogenic fusions of EML4 and ALK occur in ~5% of lung adenocarcinomas. EML4- ALK variants have distinct breakpoints within EML4, but the functional differences among these variants remain poorly understood. Here we use CRISPR/Cas9 somatic genome editing to generate autochthonous mouse models of the two most common EML4-ALK variants and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth in vivo we show that many tumor suppressor genes have dramatically variant-specific effects on tumorigenesis. Pharmacogenomic analyses suggest that tumor genotype can also modify responses to therapy. Analysis of a large human EML4-ALK lung cancer cohort identified differences in the genomic landscape depending on the EML4-ALK variant. These findings demonstrate functional heterogeneity between EML4-ALK variants, suggesting that EML4-ALK variants behave more like distinct oncogenes than a uniform entity. More broadly, these findings highlight the dramatic impact of oncogenic fusions partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion driven cancer.
2025-08-06 | GSE301214 | GEO
Project description:Oncogenic fusions of EML4 and ALK occur in ~5% of lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but the functional differences among these variants remain poorly understood. Here we use CRISPR/Cas9 somatic genome editing to generate autochthonous mouse models of the two most common EML4-ALK variants and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth in vivo we show that many tumor suppressor genes have dramatically variant-specific effects on tumorigenesis. Pharmacogenomic analyses suggest that tumor genotype can also modify responses to therapy. Analysis of a large human EML4-ALK lung cancer cohort identified differences in the genomic landscape depending on the EML4-ALK variant. These findings demonstrate functional heterogeneity between EML4-ALK variants, suggesting that EML4-ALK variants behave more like distinct oncogenes than a uniform entity. More broadly, these findings highlight the dramatic impact of oncogenic fusions partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion driven cancer.
2025-08-12 | GSE302650 | GEO
Project description:EML4-ALK variant-specific genetic interactions shape lung tumorigenesis
| PRJNA1291647 | ENA
Project description:To characterize the effects of common ALK fusion genes, we performed a comprehensive RNA-Seq analysis of NL20 cells induced with ALK-EML4-V1, ALK-EML4-V3, ALK-TFG, ALK-KIF5B, using Doxycycline
2022-12-18 | E-MTAB-11304 | biostudies-arrayexpress
Project description:We demonstrate that EML4-ALK siRNAs significantly reduced cell viability in EML4-ALK postive lung cancer cell lines,while overexpression of EML4-ALK increased cell viability in HEK293 cells in vitro. The aim of this study was to analyze the EML4-ALK regulated gene expression in lung cancer.
2021-05-20 | GSE174772 | GEO
Project description:Heat Shock Protein 90 inhibitors (HSP90i) have shown encouraging activity in EML4-ALK+ non-small cell lung cancer (NSCLC) patients but clinical responses have been heterogeneous. It has been suggested that distinct EML4-ALK variants may have a differential impact on the response to HSP90 inhibition. Here, we show that NSCLC cells harboring the most common EML4-ALK variant 1 (v1) or variant 3 (v3) are similarly sensitive to HSP90i. To discover new genetic alterations that could be involved in stratifying sensitivity, we performed a genome-wide CRISPR/Cas9 knockout screen and found that loss of Spindly increases the sensitivity of EML4-ALK v3, but not v1, NSCLC cells to low concentrations of HSP90i from three distinct chemical families. Upon loss of Spindly, prolonged exposure to low concentrations of HSP90i impairs chromosome congression and cellular fitness. Collectively, our data suggest that mutations leading to loss of Spindly in EML4-ALK v3 NSCLC patients may increase sensitivity to low doses of HSP90i.
2025-02-01 | GSE197655 | GEO
Project description:A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Despite excellent initial responses in patients, acquired resistance to ALK inhibitors occurs. Exploring these mechanisms of resistance, we found that EML4-ALK cells resistant to ALK inhibitors are remarkably sensitive to THZ1, alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. In conclusion, this study shows that THZ1, alvocidib or dinaciclib could be a therapeutic option for a subset of patients with acquired resistance to first, second and third-generation ALK inhibitors.
2019-12-15 | E-MTAB-8563 | biostudies-arrayexpress
Project description:A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Despite excellent initial responses in patients, acquired resistance to ALK inhibitors occurs. Exploring these mechanisms of resistance, we found that EML4-ALK cells resistant to ALK inhibitors are remarkably sensitive to THZ1, alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. In conclusion, this study shows that THZ1, alvocidib or dinaciclib could be a therapeutic option for a subset of patients with acquired resistance to first, second and third-generation ALK inhibitors.
2019-12-22 | E-MTAB-8590 | biostudies-arrayexpress
Project description:We demonstrate that STAT3 and STAT6 significantly activated after IL4 treatment in EML4-ALK postive lung cancer cell lines The aim of this study was to explore whether IL4 could activate the JAK2-STAT pathway in EML4-ALK-positive cells.
2021-05-19 | GSE174596 | GEO
Project description:First line treatment for EML4-ALK fusion-positive lung cancer patient is the use of an ALK tyrosine kinase inhibitor (TKI), such as alectinib. While most patients initially respond to this therapy, many patients often develop relapse, and efficacious therapies for patients with relapse disease are limited. To study EML4-ALK fusion-positive lung cancer, novel murine lung cancer cell lines were generated from C57BL/6 mice using an intratracheally injected Adeno-virus that contains Cas9 and guide RNAs for the EML4-ALK translocation, which leads to the development of lung tumors. Cell lines were derived from these tumors. In an effort to better understand how cells respond to alectinib, we treated EML4-ALK-positive murine cell lines (EA1, EA2, and EA3 cells) in vitro for 1-7 days with either 100nM alectinib or DMSO-control. At each time point, RNA was isolated from each condition. RNA was submitted to RNA-seq. Differential analysis on the RNA-seq data was performed to determine and track gene changes over time between control and treated cells. These data will allow us to better develop novel therapeutics to use in conjunction with alectinib when treating EML4-ALK fusion-positive patients.
2022-11-05 | GSE217115 | GEO