We demonstrate that FBXL2 is an E3 ubiquitin ligase targeting wild-type EGFR, EGFR activating mutants (L858R or 19del), and EGFR TKI-resistant mutants (including EGFR T790M or T790M/C797S) for proteasomal degradation, resulting in inhibition of both tumor growth and TKI resistance in vitro and in vivo. This evidence concerns the gene FBXL2 and neoplasm.