Abstract
Protein kinases are crucial targets for cancer treatment as they orchestrate important signals for oncogenesis and are often aberrantly activated owing to genomic alterations. In the past two decades, multiple kinase inhibitors have been developed, including those that are clinically effective regardless of tumour location, provided that the tumour harbours the aberrantly activated kinase. Consequently, a biomarker-based therapy model, untethered from tumour histology and organ of origin, has been established, which has led to transformative regulatory approvals of tumour-agnostic kinase inhibitors such as larotrectinib, selpercatinib, dabrafenib–trametinib and pemigatinib. However, almost all such approvals are partial in nature, as they do not include both solid and haematological cancers, even if the kinase inhibitor has shown activity in both. Moreover, clinical trials to assess these compounds are challenging because genomic sequencing of hundreds or thousands of tumours may be required to find eligible patients whose malignancy bears the targeted genetic alterations. In this Review, we describe the precision medicine paradigm that has successfully launched tumour-agnostic drug development, concentrating on small-molecule inhibitors that target kinase pathway aberrations, and we discuss the challenges in developing tumour‐agnostic agents.
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Acknowledgements
R.K. is funded in part by 5U01CA180888-08 and 5UG1CA233198-05.
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R.K. and J.J.A. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.
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J.J.A. serves on the advisory board of CureMatch and is a consultant for datma. R.K. has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, MedImmune, Merck Serono, Omniseq, Pfizer, Sequenom, Sysmex, Takeda and TopAlliance and from the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Daiichi, Datar Cancer Genetics, EISAI, EMD Serono, EOM Pharmaceuticals, Iylon, Jackson Laboratories, LabCorp, Lanauria Therapeutics, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Quanta Therapeutics, Recordati, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch, Inc.; serves on the Board of CureMatch and CureMetrix and XZOM, and is a co-founder of CureMatch. M.N. declares no competing interests.
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Glossary
- Basket studies
-
Trials that include various cancers based on genomic characteristics instead of tumour of origin and in which patients are pooled irrespective of cancer type.
- Cytogenetic response
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For chronic myelogenous leukaemia, a decrease in the percentage of bone marrow cells containing the disease-defining Philadelphia chromosome.
- Gatekeeper mutations
-
Mutation that occur in the gatekeeper residue of a kinase, which controls access to the pocket to which drugs bind and can lead to drug resistance.
- Haematological response
-
Improvement in blood cell levels (white blood cells, red blood cells and platelets) as a result of treatment.
- Marfanoid habitus
-
Signs resembling those of Marfan syndrome, including long limbs, slender fingers and toes, and extremely flexible joints.
- NCCN guidelines
-
The NCCN clinical guidelines comprise recommendations for the prevention, diagnosis and management of malignancies across the continuum of care. The NCCN guidelines currently apply to more than 97% of cancers affecting patients in the United States.
- Solvent-front mutations
-
Mutation that affect the conserved surface-exposed amino acid sequence that is close to the ATP-binding site of the kinase. They can reorient the surrounding residues thereby affecting ATP-binding and kinase activity, thus leading to resistance to kinase inhibitors.
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Adashek, J.J., Nikanjam, M. & Kurzrock, R. Tumour-agnostic kinase inhibitors. Nat Rev Drug Discov 24, 504–520 (2025). https://doi.org/10.1038/s41573-025-01147-y
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DOI: https://doi.org/10.1038/s41573-025-01147-y
