Emerging novel therapies in overcoming resistance to targeted therapy

The recent development of small molecule inhibitors and monoclonal antibodies that target cancer-specific oncogenic driver mutations has significantly improved the outcomes of patients with various tumour types including chronic myeloid leukemia, non-small cell lung cancer and melanoma. Despite high rates of response, most patients will relapse within the first year of targeted therapy due to drug resistance. Although multiple mechanisms of resistance have been defined, these often lead to the re-activation of oncogene-regulated signaling or the activation of compensatory survival cascades. This chapter focusses on emerging therapeutic strategies to overcome and circumvent resistance to targeted therapies, with an emphasis on metastatic melanoma. A variety of therapeutic salvage approaches are being explored, including novel targeted agents, new combination therapies and consideration of drug timing and sequencing. Improved clinical trial design, treatment of earlier stage cancer patients and sensitive real-time monitoring of patient responses and resistance are critical for improving the durability of cancer targeted therapies.