Here, we take advantage of a unique cohort of paired tumor specimens derived from 30 LUAD patients before and after the development of EGFR TKI-refractory disease progression to reveal that DARPP-32 as well as kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired EGFR TKI resistance. Here, PPP1R1B is linked to neoplasm.