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  • Review Article
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ALK in cancer: from function to therapeutic targeting

Nature Reviews Cancer volume 25, pages 359–378 (2025)Cite this article

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Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that acts as an oncogenic driver in solid and haematological malignancies in both children and adults. Although ALK-expressing (ALK+) tumours show strong initial responses to the series of ALK inhibitors currently available, many patients will develop resistance. In this Review, we discuss recent advances in ALK oncogenic signalling, together with existing and promising new modalities to treat ALK-driven tumours, including currently approved ALK-directed therapies, namely tyrosine kinase inhibitors, and novel approaches such as ALK-specific immune therapies. Although ALK inhibitors have changed the management and clinical history of ALK+ tumours, they are still insufficient to cure most of the patients. Therefore, more effort is needed to further improve outcomes and prevent the tumour resistance, recurrence and metastatic spread that many patients with ALK+ tumours experience. Here, we outline how a multipronged approach directed against ALK and other essential pathways that sustain the persistence of ALK+ tumours, together with potent or specific immunotherapies, could achieve this goal. We envision that the lessons learned from treating ALK+ tumours in the clinic could ultimately accelerate the implementation of innovative combination therapies to treat tumours driven by other tyrosine kinases or oncogenes with similar properties.

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Fig. 1: Alterations of the ALK protein in tumours are classified as fusions, point mutations and overexpression.
Fig. 2: ALK oncogenic signalling depends on the type of genetic alteration and cellular context.
Fig. 3: ALK+ cancer cells can bypass signalling blockade achieved by ALK tyrosine kinase inhibitors through both cell-intrinsic and cell-extrinsic mechanisms.
Fig. 4: The crystal structures of the kinase domain of ALK and the mutations associated with resistance to various tyrosine kinase inhibitors.
Fig. 5: ALK is a promising target for immunotherapies, owing to its oncogenicity, its spontaneous immunogenicity and that its expression is restricted to tumour cells.

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Data availability

The crystal structures used for Fig. 4 were downloaded from PDB with the following accessions: 3L9P for WT human ALK and neuroblastoma, 2XP2 for crizotinib; 3AOX for alectinib; 6MX8 for brigatinib; 4MKC of ceritinib, 4CLJ for lorlatinib; 9GBE for NVL-655. PyMol session files of the above structures with the in silico mutated residues reported in Fig. 4 are available in the public figshare repository (https://figshare.com/projects/ALK/234473).

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Acknowledgements

The authors thank N. Chamberlin for her critical reading of the text. The work has been supported by grants from the NIH/NCI R01 CA196703-01, the NIH/NCI P50 CA265826-01A1_LUNG SPORE, the LUNGevity ALK-positive Lung Cancer Research Award, the PoweRD 2 CureALK+ Lung Cancer TeamLab support, the AIRC IG 2021 — ID. 26011 project to R.C.; AIRC under IG 2019 — ID. 23146 to C.V.

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Authors and Affiliations

  1. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy

    Claudia Voena, Chiara Ambrogio & Roberto Chiarle

  2. Division of Hematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy

    Fabio Iannelli & Roberto Chiarle

  3. Department of Pathology, Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Roberto Chiarle

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  1. Claudia Voena
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  2. Chiara Ambrogio
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All authors researched data for the article. R.C., C.A. and C.V. contributed substantially to discussion of the content. R.C., C.A. and C.V. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Claudia Voena or Roberto Chiarle.

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R.C. is the founder and consultant of ALKEMIST Bio. C.V., F.I. and C.A. declare no conflict of interest.

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Nature Reviews Cancer thanks Keith Ligon, Aaron Hata and Bengt Hallberg for their contribution to the peer review of this work.

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Glossary

Antibody–drug conjugates

(ADC). Targeted therapies that link an antibody to a cytotoxic drug, delivering the drug specifically to cancer cells by binding to the antigen expressed on their surface.

Basket trials

Clinical trials that test the effectiveness of a single drug or treatment on multiple types of cancer that share a common genetic mutation, regardless of the cancer cell of origin or cancer type.

Breakpoint variants

Different, yet specific, locations within the same gene in which chromosomal breaks occur, leading to structural rearrangements such as translocations or fusions.

Circulating tumour DNA

(ctDNA). Fragments of DNA released into the bloodstream from cancer cells, which can be analysed to detect and monitor presence, progression and response to treatment.

Complete remission

The absence of all detectable signs of disease following cancer treatment.

Compound ALK mutants

The presence of two or more mutations within the same gene, occurring either on the same allele (cis) or different alleles (trans). They usually arise as a mechanism of resistance to targeted therapy.

Drug-tolerant persister cells

A small subpopulation of cancer cells that enter a dormant state, allowing them to survive harsh conditions or treatments, such as chemotherapy or tyrosine kinase inhibitor, and potentially cause recurrence or treatment failure.

First-line therapy

The initial treatment recommended for a particular disease or condition, typically based on its effectiveness and safety.

Oncogenic stress

A detrimental effect on tumour cell fitness that results from the overexpression or excessive activation of an oncogene, which can cause cellular stress, senescence or death, which can be exploited for cancer therapy.

Partner gene

One of the two genes involved in a fusion event, often due to chromosomal rearrangements, that can lead to abnormal gene function.

Patient-derived xenograft models

(PDX models). Models in which tumour tissue from a patient is implanted into immunodeficient mice, allowing researchers to study the tumour’s growth, drug response and biology in vivo while maintaining its original characteristics.

Steric hindrance

The prevention of chemical reactions or interactions owing to physical obstruction caused by the spatial arrangement of atoms or groups within a molecule.

Tyrosine kinase inhibitors

(TKIs). Small drugs capable of binding to the catalytic domain of a tyrosine kinase and disrupting the kinase activity and downstream signal transduction pathways.

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Voena, C., Ambrogio, C., Iannelli, F. et al. ALK in cancer: from function to therapeutic targeting. Nat Rev Cancer 25, 359–378 (2025). https://doi.org/10.1038/s41568-025-00797-9

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