Interestingly, components of the Cullin 5 (CUL5)-RING E3 ligase (CRL5) complex (such as CUL5, RNF7 and UBE2F) as well as ARIH2, an Ariadne family RING-in-Between-RING (RBR) E3 ligase working together with CRL5, were amongst the positively selected hits, suggesting their previously unrecognized role in mediating EGFR TKI resistance in lung cancer. This evidence concerns the gene CUL5 and lung cancer.