EML4 – Lung Cancer

Somatic fusions of EML4 with ALK define a recurrent molecular subset of Lung Cancer and serve as oncogenic drivers responsive to ALK tyrosine kinase inhibitors (TKIs). Initial RACE-coupled PCR sequencing in 103 non–small cell lung carcinoma (NSCLC) samples identified EML4-ALK fusions in 12 tumors (11.6%) (PMID:20624322). This fusion was enriched in adenocarcinomas lacking EGFR/KRAS mutations (16.13%; 10/62 cases) (PMID:20624322).

Multiple independent case reports confirm therapeutic efficacy of ALK inhibitors in EML4-ALK–positive patients. A rare double EML4-ALK/CDK15-ALK fusion in lung adenocarcinoma achieved a 23-month progression-free survival on crizotinib (PMID:33157918). Similarly, patients harboring EML4-ALK variants V1 and V3 exhibited durable responses to alectinib and lorlatinib following sequential ALK-TKI therapy (PMID:39430483; PMID:34520436).

Functional studies demonstrate that EML4-ALK fusion proteins possess constitutive kinase activity leading to downstream activation of MAPK, JAK–STAT, and PI3K–AKT pathways. In vitro expression of EML4-ALK p.Lys398Arg drives ALK autophosphorylation and oncogenic transformation in 293T cells, whereas splicing isoforms lacking the fusion (e.g., p.Thr1312fsTer0) are nonfunctional and do not confer crizotinib resistance when coexpressed (PMID:30010043; PMID:24419423).

Liquid biopsy analyses corroborate tissue findings, detecting EML4-ALK alterations in plasma with 100% concordance in 29 patients, supporting minimally invasive fusion screening when tumor specimens are limited (PMID:36422072).

Despite the presence of rare splice variants, the canonical EML4-ALK fusion remains the primary oncogenic driver and biomarker for targeted intervention. Emerging cell-line models derived from patient tumors (e.g., CUTO8, CUTO29) further validate differential ALK-TKI sensitivities across EML4-ALK variants, highlighting the need for variant‐specific monitoring in therapeutic planning (PMID:35933914).

Given the consistent prevalence, mechanistic oncogenicity, and robust clinical responses to ALK inhibitors, routine detection of EML4-ALK fusions is essential for precision management of lung cancer.

Key Take-home: Testing for EML4-ALK fusions is critical to identify lung cancer patients who will benefit from ALK-targeted therapies.

References

• Molecular cancer • 2010 • Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. PMID:20624322
• Medicine • 2020 • A rare double ALK fusion variant EML4-ALK and CDK15-ALK in lung adenocarcinoma and response to crizotinib: A case report. PMID:33157918
• Heliyon • 2024 • Small intestinal metastasis in a lung adenocarcinoma patient with concurrent EML4-ALK V3 and TP53 mutations after distinct responses to tyrosine kinase inhibitors: A case report. PMID:39430483
• Anti-cancer drugs • 2022 • Sensitivity of eight types of ALK fusion variant to alectinib in ALK-transformed cells. PMID:34520436
• Journal of thoracic oncology • 2018 • CUX1-ALK, a Novel ALK Rearrangement That Responds to Crizotinib in Non-Small Cell Lung Cancer. PMID:30010043
• Journal of personalized medicine • 2022 • Preliminary Experience of Liquid Biopsy in Lung Cancer Compared to Conventional Assessment: Light and Shadows. PMID:36422072
• Lung cancer (Amsterdam, Netherlands) • 2022 • Novel human-derived EML4-ALK fusion cell lines identify ribonucleotide reductase RRM2 as a target of activated ALK in NSCLC. PMID:35933914

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