However, after the treatment of EGFR-TKI, the interactions of ERβ isoforms will induce the EGFR-TKI resistance by activating non-genomic signaling pathway (such as ERK1/2 and AKT) especially in EGFR mutant lung cancer cells with co-expression of ERβ1 and other ERβ isoforms (ERβ2 or ERβ5). The gene discussed is ESR2; the disease is lung cancer.