In contrast, ablating Fbxo45 maintains the STEP46 activity to abolish the aberrant ERK1/2 signaling, which may greatly serve the NSCLC treatment, especially by combining with EGFR‐TKIs, to offer a possible way to relieve EGFR‐TKI tolerance and improve the prognosis of NSCLC patients. Here, FBXO45 is linked to non-small cell lung carcinoma.