We depict a novel mechanism that the phosphatase STEP (an active form NP‐STEP46) was subjected to proteasome‐mediated degradation in a manner of K6‐linked poly‐ubiquitination caused by the enhanced Fbxo45 expression in NSCLC, which then sustained the ERK1/2 activity for tumor cell survival, tumor growth, and even the drug resistance (Fig. 6). Here, MAPK3 is linked to neoplasm.