Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies

Abstract

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 BCR-ABL-positive chronic myeloid leukemia. We describe specific mechanisms of primary and acquired resistance and then review emerging strategies to delay or overcome drug resistance.

Figure 1. Mechanisms of Therapeutic Resistance to Kinase Inhibitors

Resistance to targeted therapies can be classified as primary resistance or acquired resistance. Primary resistance is defined as a de novo lack of treatment response and can be mediated by tumor intrinsic factors, such as concurrent genetic alterations within the drug target or within other signaling molecules, and by patient specific factors, such as drug-drug interactions. Conversely, acquired resistance refers to disease progression after an initial response to the targeted therapy. Acquired resistance develops while the patient is still receiving the targeted therapy, implying that the tumor has developed an ‘escape’ mechanism to evade continuous blockade of the target. These ‘escape’ mechanisms include target modification (gene amplification, second site mutations, splice variants), the emergence of bypass signaling tracks, histological transformation, as well as other less well characterized mechanisms such as increased growth factor production. Examples of strategies to overcome acquired resistance, which are discussed in more detail within the text, include alternative doses or schedules of the targeted inhibitor, development of more potent ‘next generation’ inhibitors, dual blockade of the initial target with two or more target-specific agents, and combination drug strategies designed to suppress compensatory signaling loops.