Given that DARPP-32 is overexpressed and ERBB3 is activated during gefitinib treatment in EGFR-mutated NSCLC cells, we propose a mechanism of acquired resistance to EGFR TKIs in NSCLC in which DARPP-32 mediates a switch from EGFR TKI-sensitive EGFR homodimers to TKI-resistant EGFR:ERBB3 heterodimers. This evidence concerns the gene EGFR and non-small cell lung carcinoma.