SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy

• DOI: 10.1016/j.ccell.2020.04.014
• Publication Date: 2020-05-21T14:37:11Z
• Authors: Zhentian Wang; Simone Hausmann; Ruitu Lyu; Tie-Mei Li; Shane M. Lofgren; Natasha M. Flores; Mary E. Fuentes; Marcello Caporicci; Ze Yang; Matthew Joseph Me...; Marcus Adrian Cheek; Sarah Ann Howard; Lichao Zhang; Joshua Eric Elias; Michael P. Kim; Anirban Maitra; Huamin Wang; Michael Cory Bassik; Michael-Christoph...; Julien Sage; Or Gozani; Pawel K. Mazur
• Keywords: 0301 basic medicine; MAP Kinase Kinase 2; MAP Kinase Kinase 1; Apoptosis; Histone-Lysine N-Methyltransferase; Methyltransferases; Mice, SCID; Chromatin; Histone Deacetylases; 3. Good health; Mice, Inbred C57BL; Pancreatic Neoplasms; Mice; 03 medical and health sciences; Drug Resistance, Neoplasm; Mice, Inbred NOD; Histocompatibility Antigens; Animals; Humans; Female; Molecular Targeted Therapy; Carcinoma, Pancreatic Ductal; Cell Proliferation

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.