Novel PLEC-EML4-ALK Double Fusion Underlying Crizotinib Resistance in a Metastatic Inflammatory Myofibroblastic Tumor: A Case Report

Alessandra Maleddu, MD; Trista K. Hinz, MS; Margaret A. Black, MD; Dara L. Aisner, MD, PhD; Carrie B. Marshall, MD; Anthony D. Elias, MD; Breelyn A. Wilky, MD; Lynn E. Heasley, PhD; Kurtis D. Davies, PhD

JTO Clinical and Research Reports (May 2025)

Novel PLEC-EML4-ALK Double Fusion Underlying Crizotinib Resistance in a Metastatic Inflammatory Myofibroblastic Tumor: A Case Report

Alessandra Maleddu, MD,
Trista K. Hinz, MS,
Margaret A. Black, MD,
Dara L. Aisner, MD, PhD,
Carrie B. Marshall, MD,
Anthony D. Elias, MD,
Breelyn A. Wilky, MD,
Lynn E. Heasley, PhD,
Kurtis D. Davies, PhD

Affiliations

Alessandra Maleddu, MD: Department of Medicine, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Trista K. Hinz, MS: Department of Craniofacial Biology, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Margaret A. Black, MD: Department of Pathology, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Dara L. Aisner, MD, PhD: Department of Pathology, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Carrie B. Marshall, MD: Department of Pathology, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Anthony D. Elias, MD: Department of Medicine, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Breelyn A. Wilky, MD: Department of Medicine, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Lynn E. Heasley, PhD: Department of Craniofacial Biology, University of Colorado – Anschutz Medical Campus, Aurora, Colorado
Kurtis D. Davies, PhD: Department of Pathology, University of Colorado – Anschutz Medical Campus, Aurora, Colorado; Corresponding author. Address for correspondence: Kurtis D. Davies, PhD, Department of Pathology, University of Colorado – Anschutz Medical Campus, BioScience 2 Room 4105, 12705 E Montview Blvd, Aurora 80045, Colorado.

Journal volume & issue: Vol. 6, no. 5
p. 100791

Abstract

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ALK fusions are frequent oncogenic drivers in inflammatory myofibroblastic tumors. Treatment with crizotinib is effective in fusion-positive patients; however, acquired resistance remains a challenge. Here, we present a case of EML4-ALK-positive metastatic inflammatory myofibroblastic tumor that initially responded to crizotinib but developed resistance. The progressing lesion revealed the acquisition of a “double fusion” event in which EML4-ALK was additionally fused to PLEC to create a PLEC-EML4-ALK transcript. The double fusion was associated with an increase in ALK expression, mimicking the ALK fusion amplification that is a known mechanism of resistance to crizotinib in lung cancer. On transition to the more potent ALK inhibitor alectinib, the patient exhibited a dramatic response. Thus, the formation of a double fusion represents a novel and targetable mechanism of resistance to crizotinib.

Published in JTO Clinical and Research Reports

ISSN: 2666-3643 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/jto-clinical-and-research-reports/

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