Acquired resistance to TKIs in solid tumours: learning from lung cancer

Camidge, D. Ross; Pao, William; Sequist, Lecia V.

doi:10.1038/nrclinonc.2014.104

Cited by 862Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentCancer Genomics and Diagnostics

Acquired resistance to TKIs in solid tumours: learning from lung cancer

Camidge, D. Ross, Pao, William, Sequist, Lecia V.·2014·Nature Reviews Clinical Oncology

DOI 10.1038/nrclinonc.2014.104

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Abstract

The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine kinase inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized the treatment of this disease. However, acquired resistance, defined as progression after initial benefit, to targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangement-positive disease, which may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. Mechanisms of acquired resistance may be pharmacological (that is, failure of delivery of the drug to its target) or biological, resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches can maintain control of the disease in the acquired resistance setting, including the use of radiation to treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. Furthermore, novel approaches that have already proven successful include the development of second-generation and third-generation inhibitors and the combination of some of these inhibitors with antibodies directed against the same target. With our increased understanding of the spectrum of acquired resistance, major changes in how we conduct clinical research in this setting are now underway.

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Authors: Camidge, D. R., Pao, W., & Sequist, L. V.
Affiliations: University of Colorado Cancer Center (US)
Vanderbilt-Ingram Cancer Center (US)
Harvard University (US)
Corresponding author: Camidge, D. Ross
ORCID: Camidge, D. Ross
Pao, William
Sequist, Lecia V.
Venue: Nature Reviews Clinical Oncology
Publisher: Springer Science and Business Media LLC
Published: 2014-07-01
Volume: 11
Issue: 8
Pages: 473-481
ISSN: 1759-4774 (ISSN-L)
1759-4782
DOI: 10.1038/nrclinonc.2014.104
OpenAlex: W1990013637
Cited by: 862
References: 14
Citations by year: 2026: 32 · 2025: 32 · 2024: 50 · 2023: 44 · 2022: 65 · 2021: 93 · 2020: 95 · 2019: 99 · 2018: 98 · 2017: 101 · 2016: 69 · 2015: 73 · 2014: 8 · 2013: 1
FWCI: 14.32
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: acquired drug resistance, tyrosine kinase inhibitors, non-small cell lung cancer, EGFR mutation, ALK rearrangement, oncogene addiction, solid tumors, second-generation TKIs, third-generation TKIs, antibody-drug conjugates, targeted therapy, radiotherapy, cytotoxic chemotherapy, molecular profiling, tumor evolution
MeSH terms: Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Protein-Tyrosine Kinases, Drug Resistance, Neoplasm, Protein Kinase Inhibitors

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Acquired resistance to TKIs in solid tumours: learning from lung cancer

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