---
title: "Three decades of anaplastic lymphoma kinase (ALK): physiology, cancer roles, and immune evasion"
id: "pubmed-42616237"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42616237"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42616237/"
doi: "10.1007/s10555-026-10364-9"
published_at: "2026-08-19T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Three decades of anaplastic lymphoma kinase (ALK): physiology, cancer roles, and immune evasion
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42616237
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42616237/)
- **DOI:** [10.1007/s10555-026-10364-9](https://doi.org/10.1007%2Fs10555-026-10364-9)
- **Published At:** 2026-08-19T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The review summarizes 30 years of research on **anaplastic lymphoma kinase (ALK)**, a receptor tyrosine kinase structurally related to the insulin receptor subfamily. - ALK has key physiological functions, notably in **neural development** and regulation of body weight and thinness in model systems and humans. - Beyond development, ALK is implicated as a driver of **systemic inflammation** and can contribute to **lethal sepsis**. - ALK’s oncogenic potential was first identified in 1994 in anaplastic large-cell lymphoma (a rare, aggressive T-cell lymphoma) where it is aberrantly expressed. - Aberrant ALK expression and activation have since been found in multiple neoplasms, including **non-small cell lung cancer**, neuroblastoma, and inflammatory myofibroblastic tumors. - In malignancies, **ALK** promotes tumor cell survival and proliferation by activating a broad network of upstream and downstream signaling pathways. - The clinical development of selective **ALK inhibitors** transformed treatment approaches for ALK-expressing cancers, especially in non-small cell lung cancer. - More recent evidence links ALK to disruption of immune system integrity and to mechanisms that sustain **immune evasion** in tumors. - The review provides an overview of physiological and pathological roles, current clinical utilization of ALK-targeted therapy, and discusses mechanisms of resistance to ALK inhibitors. - Specific details such as names of individual inhibitors, resistance mutations, and quantitative outcomes were not reported in the abstract and require consultation of the full text or references for granular data.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA. hamin@mdanderson.org. * 2 MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. hamin@mdanderson.org. * 3 Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA. * 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. * PMID: **42616237** * DOI: [ 10.1007/s10555-026-10364-9 ](https://doi.org/10.1007/s10555-026-10364-9) Item in Clipboard Review # Three decades of anaplastic lymphoma kinase: from physiological roles to cancer and immune evasion Hesham M Amin et al. Cancer Metastasis Rev. 2026. Show details Display options Display options Format Abstract PubMed PMID Cancer Metastasis Rev Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cancer+Metastasis+Rev%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Cancer+Metastasis+Rev%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) . 2026 Aug 19;45(3):61. doi: 10.1007/s10555-026-10364-9. ### Authors [Hesham M Amin](https://pubmed.ncbi.nlm.nih.gov/?term=Amin+HM&cauthor_id=42616237)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616237/#short-view-affiliation-1 "Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA. hamin@mdanderson.org.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42616237/#short-view-affiliation-2 "MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. hamin@mdanderson.org."), [Shiva Aminnia](https://pubmed.ncbi.nlm.nih.gov/?term=Aminnia+S&cauthor_id=42616237)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42616237/#short-view-affiliation-3 "Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA."), [Mona M Saber](https://pubmed.ncbi.nlm.nih.gov/?term=Saber+MM&cauthor_id=42616237)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42616237/#short-view-affiliation-4 "Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt."), [Mahesh Kumar Kannan](https://pubmed.ncbi.nlm.nih.gov/?term=Kannan+MK&cauthor_id=42616237)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42616237/#short-view-affiliation-3 "Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA."), [Justin Hung](https://pubmed.ncbi.nlm.nih.gov/?term=Hung+J&cauthor_id=42616237)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42616237/#short-view-affiliation-3 "Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA.") ### Affiliations * 1 Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA. hamin@mdanderson.org. * 2 MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. hamin@mdanderson.org. * 3 Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Unit 0072, 1515 Holcombe Boulevard, Houston, TX, USA. * 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. * PMID: **42616237** * DOI: [ 10.1007/s10555-026-10364-9 ](https://doi.org/10.1007/s10555-026-10364-9) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase with structural criteria shared among members of the insulin receptor subfamily. ALK plays crucial physiological roles such as in neural tissue development as well as in thinness and body weight regulation. In addition, ALK is a key driver of systemic inflammation that may lead to lethal sepsis. The oncogenic potential of ALK was first described in 1994 when 2 independent research groups discovered that ALK is aberrantly expressed in a rare aggressive subtype of T-cell lymphoma descriptively known as anaplastic large-cell lymphoma. Later, it was found that the aberrant expression of ALK extends to include other neoplasms such as non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumors, and others. In these neoplasms, ALK plays a central oncogenic role by upregulating the activity of a comprehensive network of upstream and downstream survival systems, which causes tumor cell survival and proliferation. The development of selective ALK inhibitors has led to paradigm shift in how ALK-expressing tumors, particularly non-small cell lung cancer, are treated. More recently, ALK has been implicated in disturbing the integrity of the immune system and sustaining immune evasion. In this review, we highlight 3 decades of ALK research, briefly discuss its physiological and pathological roles with a focus on cancer and immunity, and provide an update on the clinical utilization and mechanisms of resistance to ALK inhibitors. **Keywords:** Immune evasion; Lethal sepsis; Oncogenes; Targeted therapy; Thinness. © 2026. The Author(s). [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declarations. Competing interests: The authors have no competing financial or non-financial interests to disclose that are relevant to the content of this article. Clinical trial number: Not applicable. ## References 1. 1. Souttou, B., Carvalho, N. B., Raulais, D., & Vigny, M. (2001). Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway. Journal of Biological Chemistry, 276(12), 9526–9531. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/11121404/) - [DOI](https://doi.org/10.1074/jbc.m007333200) 2. 1. Cheng, L. Y., Bailey, A. P., Leevers, S. J., Ragan, T. J., Driscoll, P. C., & Gould, A. P. (2011). Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila. Cell, 146(3), 435–47. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/21816278/) - [DOI](https://doi.org/10.1016/j.cell.2011.06.040) 3. 1. Fadeev, A., Mendoza-Garcia, P., Irion, U., Guan, J., Pfeifer, K., Wiessner, S., et al. (2018). ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells. Proceedings of the National Academy of Sciences of the United States of America, 115(4), E630-e8. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/29317532/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/5789956/) 4. 1. Hallberg, B., & Palmer, R. H. (2016). The role of the ALK receptor in cancer biology. Annals of Oncology, 27, iii4–iii15. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/27573755/) - [DOI](https://doi.org/10.1093/annonc/mdw301) 5. 1. Iwahara, T., Fujimoto, J., Wen, D., Cupples, R., Bucay, N., Arakawa, T., et al. (1997). Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene, 14(4), 439–49. - [DOI](https://doi.org/10.1038/sj.onc.1200849) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/9053841/) Show all 285 references ## Publication types * Review Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Review%22%5Bpt%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Review) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) ## MeSH terms * Anaplastic Lymphoma Kinase* / antagonists & inhibitors Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Anaplastic+Lymphoma+Kinase%2Fantagonists+and+inhibitors%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Anaplastic+Lymphoma+Kinase) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Anaplastic Lymphoma Kinase* / genetics Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Anaplastic+Lymphoma+Kinase%2Fgenetics%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Anaplastic+Lymphoma+Kinase) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Anaplastic Lymphoma Kinase* / metabolism Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Anaplastic+Lymphoma+Kinase%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Anaplastic+Lymphoma+Kinase) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Humans Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Humans) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Immune Evasion Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Immune+Evasion%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Immune+Evasion) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Neoplasms* / drug therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Neoplasms%2Fdrug+therapy%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Neoplasms* / enzymology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Neoplasms%2Fenzymology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Neoplasms* / immunology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Neoplasms%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Neoplasms* / pathology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Neoplasms%2Fpathology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Protein Kinase Inhibitors / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Protein+Kinase+Inhibitors%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Protein+Kinase+Inhibitors) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616237/) * Protein Kinase Inhibitors / therapeutic use Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Protein+Kinase+Inhibitors%2Ftherapeutic+use%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Prot
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