Molecular Pathways Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies

The development of targeted therapies has revolutionized the treatment of cancer patients. The identification of "druggable" oncogenic kinases and the creation of small-molecule inhibitors designed to specifically target these mutant kinases have become an important therapeutic paradigm across several different malignancies. Often these inhibitors induce dramatic clinical responses in molecularly defined cohorts. However, resistance to such targeted therapies is an inevitable consequence of this therapeutic approach. Resistance can be either primary (de novo) or acquired. Mechanisms leading to primary resistance may be categorized as tumor intrinsic factors or as patient/drug-specific factors. Acquired resistance may be mediated by target gene modification, activation of "bypass tracks" that serve as compensatory signaling loops, or histologic transformation. This brief review is a snapshot of the complex problem of therapeutic resistance, with a focus on resistance to kinase inhibitors in EGF receptor mutant and ALK rearranged non–small cell lung cancer, BRAF-mutant melanoma, and BCRABL–positive chronic myeloid leukemia. We describe specific mechanisms of primary and acquired resistance and then review emerging strategies to delay or overcome drug resistance. Clin Cancer Res; 20 (9); 2249–56. 2014 AACR. Disclosure of Potential Conflicts of Interest C.M. Lovly reports receiving speakers bureau honoraria from Abbott Molecular and Qiagen and is a consultant/advisory board member for Pfizer. A.T. Shaw is a consultant/advisory board member for Ariad, Genentech, Novartis, and Pfizer. CME Staff Planners' Disclosures The members of the planning committee have no real or apparent conflict of interest to disclose.