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ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression

Tzu-Po Chuang, Wei-Yun Lai, Jonatan Linus Gabre (UGent) , Dan E. Lind, Ganesh Umapathy, Abdulmalik A. Bokhari, Bengt Bergman, Linnea Kristenson, Fredrik B. Thorén, Anh Le, et al.
(2023) PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 120(8).
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Abstract
Anaplastic lymphoma kinase (ALK) fusion variants in Non-Small Cell Lung Cancer (NSCLC) consist of numerous dimerizing fusion partners. Retrospective investigations suggest that treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs dependent on the fusion variant present in the patient tumor. Therefore, under -standing the oncogenic signaling networks driven by different ALK fusion variants is important. To do this, we developed controlled inducible cell models expressing either Echinoderm Microtubule Associated Protein Like 4 (EML4)-ALK-V1, EML4-ALK-V3, Kinesin Family Member 5B (KIF5B)-ALK, or TRK-fused gene (TFG)-ALK and investi-gated their transcriptomic and proteomic responses to ALK activity modulation together with patient-derived ALK-positive NSCLC cell lines. This allowed identification of both common and isoform-specific responses downstream of these four ALK fusions. An inflammatory signature that included upregulation of the Serpin B4 serine protease inhibitor was observed in both ALK fusion inducible and patient-derived cells. We show that Signal transducer and activator of transcription 3 (STAT3), Nuclear Factor Kappa B (NF-kappa B) and Activator protein 1 (AP1) are major transcriptional regulators of SERPINB4 downstream of ALK fusions. Upregulation of SERPINB4promotes survival and inhibits natural killer cell-mediated cytotoxicity, which has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
Keywords
Multidisciplinary, phosphoprofiling, NGS, ALK fusion, anaplastic lymphoma kinase, non-small cell lung cancer

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MLA
Chuang, Tzu-Po, et al. “ALK Fusion NSCLC Oncogenes Promote Survival and Inhibit NK Cell Responses via SERPINB4 Expression.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 120, no. 8, Proceedings of the National Academy of Sciences, 2023, doi:10.1073/pnas.2216479120.
APA
Chuang, T.-P., Lai, W.-Y., Gabre, J. L., Lind, D. E., Umapathy, G., Bokhari, A. A., … Hallberg, B. (2023). ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 120(8). https://doi.org/10.1073/pnas.2216479120
Chicago author-date
Chuang, Tzu-Po, Wei-Yun Lai, Jonatan Linus Gabre, Dan E. Lind, Ganesh Umapathy, Abdulmalik A. Bokhari, Bengt Bergman, et al. 2023. “ALK Fusion NSCLC Oncogenes Promote Survival and Inhibit NK Cell Responses via SERPINB4 Expression.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120 (8). https://doi.org/10.1073/pnas.2216479120.
Chicago author-date (all authors)
Chuang, Tzu-Po, Wei-Yun Lai, Jonatan Linus Gabre, Dan E. Lind, Ganesh Umapathy, Abdulmalik A. Bokhari, Bengt Bergman, Linnea Kristenson, Fredrik B. Thorén, Anh Le, Robert C. Doebele, Jimmy Van den Eynden, Ruth H. Palmer, and Bengt Hallberg. 2023. “ALK Fusion NSCLC Oncogenes Promote Survival and Inhibit NK Cell Responses via SERPINB4 Expression.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120 (8). doi:10.1073/pnas.2216479120.
Vancouver
1.
Chuang T-P, Lai W-Y, Gabre JL, Lind DE, Umapathy G, Bokhari AA, et al. ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2023;120(8).
IEEE
[1]
T.-P. Chuang et al., “ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression,” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 120, no. 8, 2023.
@article{01GSD95R5R4D59P5KX7QPQXMPZ,
  abstract     = {{Anaplastic lymphoma kinase (ALK) fusion variants in Non-Small Cell Lung Cancer (NSCLC) consist of numerous dimerizing fusion partners. Retrospective investigations suggest that treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs dependent on the fusion variant present in the patient tumor. Therefore, under -standing the oncogenic signaling networks driven by different ALK fusion variants is important. To do this, we developed controlled inducible cell models expressing either Echinoderm Microtubule Associated Protein Like 4 (EML4)-ALK-V1, EML4-ALK-V3, Kinesin Family Member 5B (KIF5B)-ALK, or TRK-fused gene (TFG)-ALK and investi-gated their transcriptomic and proteomic responses to ALK activity modulation together with patient-derived ALK-positive NSCLC cell lines. This allowed identification of both common and isoform-specific responses downstream of these four ALK fusions. An inflammatory signature that included upregulation of the Serpin B4 serine protease inhibitor was observed in both ALK fusion inducible and patient-derived cells. We show that Signal transducer and activator of transcription 3 (STAT3), Nuclear Factor Kappa B (NF-kappa B) and Activator protein 1 (AP1) are major transcriptional regulators of SERPINB4 downstream of ALK fusions. Upregulation of SERPINB4promotes survival and inhibits natural killer cell-mediated cytotoxicity, which has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.}},
  articleno    = {{e2216479120}},
  author       = {{Chuang, Tzu-Po and Lai, Wei-Yun and Gabre, Jonatan Linus and Lind, Dan E. and Umapathy, Ganesh and Bokhari, Abdulmalik A. and Bergman, Bengt and Kristenson, Linnea and Thorén, Fredrik B. and Le, Anh and Doebele, Robert C. and Van den Eynden, Jimmy and Palmer, Ruth H. and Hallberg, Bengt}},
  issn         = {{0027-8424}},
  journal      = {{PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}},
  keywords     = {{Multidisciplinary,phosphoprofiling,NGS,ALK fusion,anaplastic lymphoma kinase,non-small cell lung cancer}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{12}},
  publisher    = {{Proceedings of the National Academy of Sciences}},
  title        = {{ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression}},
  url          = {{http://doi.org/10.1073/pnas.2216479120}},
  volume       = {{120}},
  year         = {{2023}},
}
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