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

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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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          Author and article information

          Journal
          Nat Rev Clin Oncol
          Nature reviews. Clinical oncology
          Springer Nature
          1759-4782
          1759-4774
          Aug 2014
          : 11
          : 8
          Affiliations
          [1 ] University of Colorado Comprehensive Cancer Center, Mailstop F704, Anschutz Cancer Pavilion Room 5327, Anschutz Medical Campus, Aurora, CO 80045, USA.
          [2 ] Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN 37232, USA.
          [3 ] Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
          Article
          nrclinonc.2014.104
          10.1038/nrclinonc.2014.104
          24981256

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