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

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Key Points

  • Oncogene-addicted subtypes of non-small-cell lung cancer (NSCLC), with dramatic responses to tyrosine kinase inhibitors (TKIs) are well recognized, with EGFR mutant and ALK rearrengement being two prominent examples

  • Acquired resistance after initial clinical benefit inevitably occurs, usually within 1–2 years of starting therapy

  • Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TKI exposure

  • Treatment approaches to acquired resistance include use of local ablative therapies to sites of progression and continuation of TKIs, cytotoxic chemotherapy or, if available, change in relevant targeted therapy

  • Clinical trials of acquired resistance in the future may have to consider the importance of the CNS as a sanctuary site

  • Trials of acquired resistance should consider the re-emergence of disease sensitive to the original TKI if there is an intervening period when the TKI-specific resistance selection pressure is relaxed

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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Figure 1: Mechanisms of acquired resistance to TKIs in oncogene-addicted cancers.
Figure 2: Mechanisms of biological acquired resistance.
Figure 3: Clinical approaches for patients with acquired resistance.

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All authors contributed equally to this article, including discussion of content, writing, and editing the manuscript before submission and after peer review.

Correspondence to D. Ross Camidge.

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Camidge, D., Pao, W. & Sequist, L. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 11, 473–481 (2014) doi:10.1038/nrclinonc.2014.104

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