2018
DOI: 10.1200/jco.2017.76.2294
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Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer

Abstract: Advanced anaplastic lymphoma kinase (ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and MethodsWe identified 129 patients with ALK-positive NSCLC with known ALK variants… Show more

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Cited by 273 publications
(283 citation statements)
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“…Although FISH remains gold standard for fusion detection, other RNA-based assays such as the targeted NGS used here or Nanostring show higher predictive value for response to treatment. 35 Along the same lines, other recent studies have reported an increased frequency of ALK resistance mutations in V3-positive NSCLC, 36 as well as a worse PFS for V3-driven TKI-treated tumors. This is becoming increasingly important, because accumulating data suggest that several fusion variants have prognostic and predictive significance.…”
Section: Discussionmentioning
confidence: 76%
“…Although FISH remains gold standard for fusion detection, other RNA-based assays such as the targeted NGS used here or Nanostring show higher predictive value for response to treatment. 35 Along the same lines, other recent studies have reported an increased frequency of ALK resistance mutations in V3-positive NSCLC, 36 as well as a worse PFS for V3-driven TKI-treated tumors. This is becoming increasingly important, because accumulating data suggest that several fusion variants have prognostic and predictive significance.…”
Section: Discussionmentioning
confidence: 76%
“…Its presence is associated with more frequent occurrence and a wider range of metastatic dissemination as well as with shorter overall survival (OS) due to earlier treatment failure with TKI, chemotherapy and cerebral radiotherapy . These observations are in line with the longer half‐life and stronger signaling of the V3 oncoprotein in vitro as well as the higher propensity of V3‐driven tumors for the development of ALK resistance mutations . At the structural level, V3 is a “short” molecule compared to the other two common EML4‐ALK variants V1 (E13A20) and V2 (E20A20), which enhances stability and could account for the higher malignant potential (Supporting Information Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Among the EML4‐ALK variants identified in previous studies, variant V1 [exon 13 of EML4 fuses to exon 20 of ALK (E13;A20)] and variant V3 [exon 6 of EML4 fuses to exon 20 of ALK (E6;A20)] have been shown to be the most predominant . Variant V3 has recently been identified as a high‐risk factor in ALK translocation‐positive lung adenocarcinoma, which is correlated with metastasis and short overall survival (OS) …”
Section: Introductionmentioning
confidence: 99%