^{Immunology and Oncology}

Targeted therapies act by blocking essential biochemical pathways or mutant proteins that are required for tumour cell growth and survival. These drugs can arrest tumour progression and induce striking regressions in molecularly defined subsets of patients. Indeed, the first small molecule targeted agent, the BCR-ABL kinase inhibitor imatinib, rapidly induced complete cytogenetic responses in 76% of chronic myelogenous leukaemia patients. Further research into the underlying genetic pathways driving tumour proliferation uncovered additional oncoproteins that are critical for tumour maintenance, such as the epidermal growth factor receptor (EGFR), BRAF, KIT, HER (also known as neu and ERBB) and anaplastic lymphoma kinase (ALK). Similar to imatinib, small molecule inhibitors of these kinases have effectuated impressive tumour responses in selected patients, although regressions are commonly followed by the development of progressive disease due to the emergence of drug-resistant variants. Resistance usually involves secondary mutations within the targeted protein or compensatory changes within the targeted pathway that bypass the drug-mediated inhibition. Accordingly, targeted therapies may elicit dramatic tumour regressions, but persistence is generally short-lived, limiting the overall clinical benefit.