PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer

• DOI: 10.1016/j.xcrm.2022.100741
• Publication Date: 2022-09-12T14:46:14Z
• Authors: Xueyan Wang; Jing Yu; Xiaowei Liu; Dan Luo; Yanchu Li; Linlin Song; Xian Jiang; Xiaomeng Yin; Yan Wang; Li Chai; Ting Luo; Jing Jing; Hubing Shi
• Keywords: MG132; Triple-negative breast cancer; Trametinib; Synthetic Lethality; Targeted Therapy

Although the MAPK pathway is aberrantly activated in triple-negative breast cancers (TNBCs), clinical outcome of MEK-targeted therapy still poor. Through a genome-wide CRISPR-Cas9 library screening, we find that inhibition PSMG2 sensitizes TNBC cells BT549 and MB468 to MEK inhibitor AZD6244. Mechanistically, knockdown impairs proteasome function, which turn activates autophagy-mediated PDPK1 degradation. The degradation significantly enhances AZD6244-induced tumor cell growth by interrupting negative feedback signals toward AKT pathway. Consistently, co-targeting proteasomes with inhibitors synergistically suppresses growth. autophagy chloroquine partially relieves reverses induced combinatorial proteasome. combination regimen MG132 plus AZD6244 inhibits 4T1 xenograft mouse model. In summary, our study not only unravels mechanism resistance but also provides therapeutic strategy for clinics.