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As shown here, Keap1-Nrf2, although an exquisitely sensitive ROS sensor, and an adaptive mechanism for treatment resistance, can be maintained in a relatively narrow range as demonstrated by the difficulties associated with exogenous molecular manipulation of either KEAP1 or NFE2L2 (in contrast to routine manipulation of other oncogenes and tumor suppressors such as TP53 , PIK3CA , NOTCH1 )