Cited by 108Lung Cancer Treatments and MutationsCancer Mechanisms and TherapyCancer Genomics and Diagnostics

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ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties

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Childress, Merrida A., Himmelberg, Stephen M., Chen, Huiqin, Deng, Wanleng, Davies, Michael A., Lovly, Christine M.·2018·Molecular Cancer Research

DOI 10.1158/1541-7786.mcr-18-0171PMC PMC6214753

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Abstract

Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 5′ fusion partner genes have been reported, treatment of ALK-rearranged cancers is decided without regard to which 5′ partner is present. There is little data addressing how the 5′ partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKI). On the basis of the hypothesis that the 5′ partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs, clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated. Biochemical and cellular assays were used to assess the efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. IC50s were calculated for different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and consistent differences (5–10 fold) in drug sensitivity were noted across the seven ALK fusions tested. Finally, biochemical analyses revealed negative correlations between kinase activity and protein stability. These results demonstrate that the 5′ fusion partner plays an important biological role that affects sensitivity to ALK TKIs. Implications: This study shows that the 5′ ALK fusion partner influences ALK TKI drug sensitivity. As many other kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies have ramifications for other kinase-driven malignancies. Mol Cancer Res; 16(11); 1724–36. ©2018 AACR.

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Authors: Childress, M. A., Himmelberg, S. M., Chen, H., Deng, W., Davies, M. A., & Lovly, C. M.
Affiliations: Vanderbilt University (US)
Vanderbilt University Medical Center (US)
The University of Texas MD Anderson Cancer Center (US)
Corresponding author: Lovly, Christine M.
ORCID: Childress, Merrida A.
Himmelberg, Stephen M.
Chen, Huiqin
Davies, Michael A.
Lovly, Christine M.
Venue: Molecular Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2018-11-01
Volume: 16
Issue: 11
Pages: 1724-1736
ISSN: 1541-7786 (ISSN-L)
1557-3125
DOI: 10.1158/1541-7786.mcr-18-0171
PMC: PMC6214753
OpenAlex: W2839057355
Cited by: 108
References: 61
Citations by year: 2026: 6 · 2025: 13 · 2024: 13 · 2023: 14 · 2022: 17 · 2021: 20 · 2020: 12 · 2019: 10 · 2018: 2
FWCI: 8.29
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Cancer Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: For the Linds Foundation
International Association for the Study of Lung Cancer (IASLC)
HHS | NIH | National Cancer Institute (NCI) (CA009592, CA16672, R01CA121210, CA213744-02)
TJ Martell Foundation
American Cancer Society (ACS) (IRG-58-009-54)
Damon Runyon Cancer Research Foundation (Damon Runyon)
LUNGevity Foundation
V Foundation for Cancer Research (V Foundation)
AACR-Genentech Career Development Award (15-20-18-LOVL)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: ALK fusion partners, anaplastic lymphoma kinase, tyrosine kinase inhibitors, drug sensitivity, kinase activity, protein stability, crizotinib, ensartinib, alectinib, lorlatinib, oncogenic transformation, soft agar colony formation
MeSH terms: Anaplastic Lymphoma Kinase, Animals, Phenotype, Oncogene Proteins, Fusion, NIH 3T3 Cells, Cell Line, Tumor, Protein Kinase Inhibitors, Mice

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ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties

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