Findings from proximity ligation assays, immunoprecipitation studies, and immunofluorescence experiments presented here support a model in which DARPP-32 mediates a switch from EGFR TKI-sensitive EGFR homodimers to TKI-resistant EGFR:ERBB3 heterodimers to potentiate oncogenic AKT and ERK signaling that drives therapy-refractory tumor cell survival. Here, PPP1R1B is linked to neoplasm.