PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK targeted therapy in TNBC

ABSTRACT: We performed an unbiased genome-wide CRISPR/Cas9 knockout screening to identify synergistic drug targets in TNBC cells with MEK inhibitor. PSMG2 was found as a critical synthetically lethal gene with MEK inhibition. Mechanism investigation unraveled that PSMG2 knockdown inhibited proteasome function, which in turn activated cell autophagy. Autophagy, unlike its function in chemoresistance, inhibited PI3K/AKT pathway by specific degradation of PDPK1. Co-targeting MAPK pathway and proteasome pathway synergistically suppressed TNBC cells proliferation in vitro and in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206748 | GEO | 2022/06/28

REPOSITORIES: GEO