RRC ID 67402
Author Wang Z, Hausmann S, Lyu R, Li TM, Lofgren SM, Flores NM, Fuentes ME, Caporicci M, Yang Z, Meiners MJ, Cheek MA, Howard SA, Zhang L, Elias JE, Kim MP, Maitra A, Wang H, Bassik MC, Keogh MC, Sage J, Gozani O, Mazur PK.
Title SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
Journal Cancer Cell
Abstract Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.
Volume 37(6)
Pages 834-849.e13
Published 2020-6-8
DOI 10.1016/j.ccell.2020.04.014
PII S1535-6108(20)30213-0
PMID 32442403
PMC PMC8187079
MeSH Animals Apoptosis Carcinoma, Pancreatic Ductal / drug therapy Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / pathology Cell Proliferation Chromatin / genetics* Drug Resistance, Neoplasm* Female Histocompatibility Antigens / genetics Histocompatibility Antigens / metabolism Histone Deacetylases / chemistry Histone Deacetylases / genetics Histone Deacetylases / metabolism Histone-Lysine N-Methyltransferase / antagonists & inhibitors Histone-Lysine N-Methyltransferase / genetics Histone-Lysine N-Methyltransferase / metabolism Humans MAP Kinase Kinase 1 / antagonists & inhibitors MAP Kinase Kinase 1 / genetics MAP Kinase Kinase 1 / metabolism MAP Kinase Kinase 2 / antagonists & inhibitors MAP Kinase Kinase 2 / genetics MAP Kinase Kinase 2 / metabolism Methyltransferases / antagonists & inhibitors Methyltransferases / genetics Methyltransferases / metabolism* Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, SCID Molecular Targeted Therapy* Pancreatic Neoplasms / drug therapy* Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology Protein Kinase Inhibitors / pharmacology* Pyridones / pharmacology Pyrimidinones / pharmacology Small Molecule Libraries / pharmacology* Tumor Cells, Cultured Xenograft Model Antitumor Assays
IF 26.602
Human and Animal Cells KP4(RCB1005)