EML4 — Lung Adenocarcinoma

The echinoderm microtubule-associated protein-like 4 (EML4) gene forms oncogenic fusions with anaplastic lymphoma kinase (ALK) defining a distinct subtype of lung adenocarcinoma. EML4-ALK fusions occur in approximately 3–7% of patients, predominantly younger, never-smokers, and are associated with mucinous cribriform or acinar histology (PMID:29535536, PMID:29952952). The first case of synchronous bilateral adenocarcinomas with EML4-ALK positivity was reported in a 55-year-old Japanese woman (PMID:23617234).

Somatic EML4-ALK rearrangements encompass over 17 variant breakpoints, with E13:A20 (variant 1), E20:A20 (variant 2), and E6:A19 among the most recurrent. Novel fusion structures include in-frame LTBP1 insertions within variant 1 junctions (PMID:29535536), E19:A20 fusions unresponsive to first-line alectinib (PMID:30133144), and double fusions (e.g., NLRC4-ALK + EML4-ALK) benefiting from crizotinib (PMID:32212216).

Inheritance is strictly somatic, with no germline segregation. No familial aggregation or affected relatives have been described.

Functional assays in patient-derived NSCLC cell lines (CUTO8, CUTO9, CUTO29, YU1077) confirm that EML4-ALK variants drive oncogenic transformation, signal via STAT3/ERK, and remain sensitive to ALK-TKIs, identifying RRM2 as a downstream target (PMID:35933914). ALK kinase domain splicing isoforms co-occur but lack transforming activity and do not confer crizotinib resistance (PMID:24419423).

Clinically, EML4-ALK–positive patients achieve high response rates to crizotinib (ongoing PFS >12 months) and alectinib, though resistance arises via G1202R and I1171N secondary ALK mutations, which respond to lorlatinib (PMID:37007089, PMID:36186223). Sequential TKI therapy can deliver prolonged disease control (>11 years of follow-up).

The fusion-driven constitutive activation of ALK tyrosine kinase establishes haploinsufficiency-independent oncogenesis. Robust clinical and cellular concordance underpins the predictive utility of EML4-ALK testing for targeted therapy decisions.

Key Take-home: Somatic EML4-ALK fusions define a targetable subset of lung adenocarcinoma with proven diagnostic and therapeutic relevance, guiding ALK-TKI selection and resistance monitoring.

References

• BMC pulmonary medicine • 2013 • A case of synchronous bilateral lung cancers: EML4-ALK positive adenocarcinoma in the right lung and adenocarcinoma in situ in the left lung. PMID:23617234
• OncoTargets and therapy • 2018 • Response to crizotinib in a non-small-cell lung cancer patient harboring an EML4-ALK fusion with an atypical LTBP1 insertion. PMID:29535536
• Medicine • 2018 • Correlation between EML4-ALK, EGFR and clinicopathological features based on IASLC/ATS/ERS classification of lung adenocarcinoma. PMID:29952952
• Lung cancer • 2022 • Novel human-derived EML4-ALK fusion cell lines identify ribonucleotide reductase RRM2 as a target of activated ALK in NSCLC. PMID:35933914
• Journal of thoracic oncology • 2014 • Identification and characterization of ALK kinase splicing isoforms in non-small-cell lung cancer. PMID:24419423
• Thoracic cancer • 2018 • Alectinib treatment response in lung adenocarcinoma patient with novel EML4-ALK variant. PMID:30133144
• International cancer conference journal • 2022 • Long-term treatment with ALK inhibitors for postoperative recurrence of ALK-rearranged lung cancer. PMID:36186223
• Frontiers in oncology • 2023 • Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report. PMID:37007089

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