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Cancer cells optimize oncogenic signaling to maintain a defined range for survival. The success of targeted therapeutic inhibitors is based on suppressing signaling below this optimal fitness zone. Conversely, cancers are also susceptible to a clinically underutilized vulnerability - oncogenic hyperactivation. Cytotoxic hyperactivation is observed across diverse cancers, with direct small-molecule activators and inhibitors of negative regulators inducing lethal pathway activation. Deep characterization of the cancer genome and unbiased screening approaches have yielded multiple targets vulnerable to hyperactivation; however, translation into the clinical setting will require defining signaling thresholds, discovering biomarkers, and developing appropriate trial designs. By exploiting cancer's intrinsic vulnerabilities, activation lethality offers a promising therapeutic strategy to expand the treatment landscape and overcome resistance to targeted inhibition.