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Target specificity and off-target effects as determinants of cancer drug efficacy

Targeted therapeutics are aimed to hit one or a few key cellular targets. Agents that target single signaling molecules (such as EGFR and IGF-R1) often show limited clinical activities, at least in the major groups of solid tumors. Nevertheless, some signaling inhibitors are effective in the treatment of previously difficult-to-treat diseases such as renal carcinoma. Similarly, these drugs inhibit multiple kinases and/or may display off-target activities. Inhibition of cellular targets such as the proteasome, heat-shock protein 90, and histone deacetylase induces complex cellular effects, and agents that inhibit these targets show promising clinical activities. Clinically effective targeted agents are therefore reminiscent of conventional agents such as cisplatin and doxorubicin, which are known to have several cellular targets. It is becoming increasingly clear that a comprehensive understanding of the spectrum of effects exerted by an anticancer agent is fundamental for understanding its efficacy and toxicity profile.