# Anaplastic lymphoma kinase
**Anaplastic lymphoma kinase** (ALK) is a receptor tyrosine kinase, a cell-surface enzyme that helps control cell growth, encoded by the ALK gene (also called anaplastic lymphoma receptor tyrosine kinase) on chromosome 2p23[1](https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anaplastic-lymphoma-kinase) • [2](https://medlineplus.gov/download/genetics/gene/alk.pdf). The gene attracts clinical attention because it is altered in several cancers: chromosomal rearrangements fuse ALK to partner genes in anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, and non-small cell lung cancer (NSCLC), while point mutations occur in neuroblastoma[1](https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anaplastic-lymphoma-kinase) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/). These changes drive cancer cell growth and spread, and they also make tumors vulnerable to a class of targeted drugs, the ALK tyrosine kinase inhibitors[1](https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anaplastic-lymphoma-kinase) • [4](https://pubmed.ncbi.nlm.nih.gov/42371103/).
| Key fact | Detail |
|---|---|
| Protein type | Receptor tyrosine kinase that helps control cell growth[1](https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anaplastic-lymphoma-kinase) |
| Gene location | Chromosome 2p23; first cloned in 1994 through the NPM-ALK fusion[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/) • [5](https://www.sciencedirect.com/science/article/pii/S0006497120604724) |
| Discovery | Identified in 1994 as the gene fused to nucleophosmin (NPM) in the t(2;5)(p23;q35) translocation of anaplastic large cell lymphoma[5](https://www.sciencedirect.com/science/article/pii/S0006497120604724) |
| Major fusion in lung cancer | EML4-ALK, discovered in 2007, from small inversions within chromosome 2p[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/) |
| Approved inhibitors | Crizotinib (approved 2011), ceritinib, alectinib, brigatinib, lorlatinib[4](https://pubmed.ncbi.nlm.nih.gov/42371103/) • [6](https://pubmed.ncbi.nlm.nih.gov/23201355/) |
| Main resistance routes | On-target kinase-domain mutations (solvent-front and gatekeeper regions) and off-target bypass signaling[4](https://pubmed.ncbi.nlm.nih.gov/42371103/) |
## Discovery in lymphoma
ALK entered the literature through a chromosomal translocation rather than through its normal function. In the late 1980s and early 1990s, several groups noted that a subset of anaplastic large cell lymphoma (ALCL), a non-Hodgkin lymphoma of T or null cell type, carried a recurrent translocation, t(2;5)(p23;q35)[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3407651/). In 1994, two independent groups cloned the genes involved and showed that the nucleophosmin (NPM) gene on chromosome 5q35 was fused to a previously unidentified gene, anaplastic lymphoma kinase, on 2p23[5](https://www.sciencedirect.com/science/article/pii/S0006497120604724).
The resulting chimeric protein, NPM-ALK, is a constitutively active tyrosine kinase. NPM contributes an N-terminal dimerization domain that promotes autophosphorylation and activation of the ALK kinase domain, which then phosphorylates downstream signaling proteins[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC3396068/). Tumors carrying this translocation became a distinct clinicopathologic entity, ALK-positive ALCL, included in the World Health Organization classification[5](https://www.sciencedirect.com/science/article/pii/S0006497120604724).
Frequency and partners. The t(2;5)(p23;q35) translocation occurs in 40% to 60% of ALCL patients by one review's account, and 80% to 85% of ALK-positive ALCL cases harbor it[5](https://www.sciencedirect.com/science/article/pii/S0006497120604724) • [8](https://pmc.ncbi.nlm.nih.gov/articles/PMC3396068/). NPM-ALK is the most common fusion in ALK-positive ALCL at 70% to 80%, followed by TPM3-ALK at 12% to 18%; other partners reported in ALCL include TFG, TPM4, ATIC, RNF213, CLTC, MSN, MYH9, and TRAF[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC6144189/). ALK immunohistochemistry plays a central role in diagnosing ALK-positive tumors[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC6144189/).
## ALK rearrangements in lung cancer and other tumors
Interest in ALK widened sharply in 2007, when a team led by [Hiroyuki Mano](https://www.edgepedia.org/hiroyuki-mano), MD, PhD, a physician-scientist then working on lung cancer genomics in Japan, described a new ALK fusion in a small percentage of Japanese lung cancers: echinoderm microtubule-associated protein-like 4 ([EML4](https://www.edgepedia.org/eml4)) fused to ALK[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/). EML4-ALK fusions result from small inversions within chromosome 2p that fuse differing portions of EML4 with a portion of ALK[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/). The EML4-ALK fusion is described as the most common and clinically significant ALK rearrangement in NSCLC, and it is one of the well-characterized oncogenic drivers of that disease[4](https://pubmed.ncbi.nlm.nih.gov/42371103/).
Two fusion variants dominate in lung cancer: variant 1 (E13;A20) and variant 3 (E6a/b;A20). They are associated with differences in protein stability, drug sensitivity, and distinct resistance mutations, and the presence of variant 3 worsens prognosis and increases the risk of metastasis[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10754274/pdf/nihms-1951735.pdf) • [4](https://pubmed.ncbi.nlm.nih.gov/42371103/).
After the discovery of EML4-ALK, ALK fusions were explored and identified in other epithelial tumors, including renal, colon, breast, ovarian, thyroid, and bladder cancer[11](https://www.jsltr.org/journal/57-3/P120-142_17023.pdf). ALK translocations had earlier been found in a subset of inflammatory myofibroblastic tumors[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/), and ALK point mutations or rearrangements also drive aberrant activation in neuroblastoma[1](https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anaplastic-lymphoma-kinase) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10754274/pdf/nihms-1951735.pdf).
## Targeted drugs
ALK rearrangements are actionable targets. Five ALK inhibitors have markedly improved outcomes in ALK-rearranged NSCLC: crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib[4](https://pubmed.ncbi.nlm.nih.gov/42371103/). The interval from discovery to drug was short by drug-development standards: the EML4-ALK fusion protein was discovered in 2007 and crizotinib was approved for ALK-positive NSCLC in 2011[6](https://pubmed.ncbi.nlm.nih.gov/23201355/). Development has since progressed through generations, culminating in the highly effective third-generation inhibitor lorlatinib[12](https://pubmed.ncbi.nlm.nih.gov/35534623/). Inhibition of ALK disrupts ALK-mediated signaling and inhibits tumor cell growth in ALK-expressing tumor cells[13](https://www.cancer.gov/publications/dictionaries/cancer-drug/def/alk-inhibitor-plb-1003).
## Drug resistance
Resistance to ALK inhibitors emerges through two broad classes of mechanism[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC5296241/):
- **On-target mechanisms**, in which the tumor remains dependent on ALK signaling. These include secondary resistance mutations in the kinase domain and ALK amplification. Mutations in the solvent-front and gatekeeper regions alter the conformation of the ATP-binding site and reduce the binding affinity of ALK inhibitors; G1202R-associated compound mutations confer high-level resistance that limits currently available inhibitors[4](https://pubmed.ncbi.nlm.nih.gov/42371103/) • [14](https://pmc.ncbi.nlm.nih.gov/articles/PMC5296241/).
- **Off-target mechanisms**, in which tumor cells escape ALK dependency. These include activation of bypass signaling pathways, often through reactivation of an upstream receptor tyrosine kinase with a signaling pattern similar to ALK, and lineage changes such as phenotypic transformation[4](https://pubmed.ncbi.nlm.nih.gov/42371103/) • [15](https://pmc.ncbi.nlm.nih.gov/articles/PMC12208075) • [12](https://pubmed.ncbi.nlm.nih.gov/35534623/).
For first-generation crizotinib, about 28% of resistance cases were related to nearly a dozen different ALK mutations in the EML4-ALK fusion protein, with the remainder attributed to upregulation of alternative signaling pathways or undefined mechanisms[6](https://pubmed.ncbi.nlm.nih.gov/23201355/). The relative frequency of each resistance mutation depends on the generation of the inhibitor and on whether it is used as first-line, second-line, or third-line therapy[15](https://pmc.ncbi.nlm.nih.gov/articles/PMC12208075). Responses under development include novel fourth-generation tyrosine kinase inhibitors and combination regimens[12](https://pubmed.ncbi.nlm.nih.gov/35534623/).
## From discovery to clinic
The ALK story illustrates a biomarker-directed treatment paradigm. The gene was cloned in 1994 as the partner of NPM in lymphoma; rearrangements were next found in inflammatory myofibroblastic tumors; and the 2007 EML4-ALK report transformed ALK into a major target in lung cancer[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/). Within four and a half years of that report, a targeted inhibitor was approved, and routine molecular profiling of lung cancers now identifies ALK-rearranged patients for targeted therapy[6](https://pubmed.ncbi.nlm.nih.gov/23201355/) • [12](https://pubmed.ncbi.nlm.nih.gov/35534623/). The remaining clinical challenge, as summarized in recent reviews, is acquired resistance, which is addressed through next-generation inhibitors designed against the known mutation spectrum[4](https://pubmed.ncbi.nlm.nih.gov/42371103/).
## References
1. [Anaplastic lymphoma kinase, NCI Dictionary of Cancer Terms, National Cancer Institute](https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anaplastic-lymphoma-kinase)
2. [ALK gene, MedlinePlus Genetics](https://medlineplus.gov/download/genetics/gene/alk.pdf)
3. [ALK in Lung Cancer: Past, Present, and Future, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4209068/)
4. [ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications, PubMed](https://pubmed.ncbi.nlm.nih.gov/42371103/)
5. [Pathobiology of ALK+ anaplastic large-cell lymphoma, Blood](https://www.sciencedirect.com/science/article/pii/S0006497120604724)
6. [Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition, PubMed](https://pubmed.ncbi.nlm.nih.gov/23201355/)
7. [NPM-ALK: The Prototypic Member of a Family of Oncogenic Fusion Tyrosine Kinases, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3407651/)
8. [ALK-immunoreactive neoplasms, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3396068/)
9. [Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6144189/)
10. [ALK-positive lung cancer: a moving target, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10754274/pdf/nihms-1951735.pdf)
11. [Anaplastic large cell lymphoma, Journal of the Korean Society of Lymphology](https://www.jsltr.org/journal/57-3/P120-142_17023.pdf)
12. [Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management, PubMed](https://pubmed.ncbi.nlm.nih.gov/35534623/)
13. [Definition of ALK inhibitor PLB 1003, NCI Drug Dictionary](https://www.cancer.gov/publications/dictionaries/cancer-drug/def/alk-inhibitor-plb-1003)
14. [Targeting ALK: Precision Medicine Takes On Drug Resistance, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5296241/)
15. [ALK in cancer: from function to therapeutic targeting, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12208075)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Diseases and injuries › Cardiovascular and blood conditions › Blood disorders (hematologic conditions) › Lymphomas › T-cell, NK-cell, and cutaneous lymphomas › Anaplastic large-cell lymphoma*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license