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

Zhentian Wang; Simone Hausmann; Ruitu Lyu; Tie-Mei Li; Shane M Lofgren; Natasha M Flores; Mary E Fuentes; Marcello Caporicci; Ze Yang; Matthew Joseph Meiners; Marcus Adrian Cheek; Sarah Ann Howard; Lichao Zhang; Joshua Eric Elias; Michael P Kim; Anirban Maitra; Huamin Wang; Michael Cory Bassik; Michael-Christopher Keogh; Julien Sage; Or Gozani; Pawel K Mazur

doi:10.1016/j.ccell.2020.04.014

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

Cancer Cell. 2020 Jun 8;37(6):834-849.e13. doi: 10.1016/j.ccell.2020.04.014. Epub 2020 May 21.

Authors

Zhentian Wang¹, Simone Hausmann², Ruitu Lyu³, Tie-Mei Li¹, Shane M Lofgren², Natasha M Flores², Mary E Fuentes², Marcello Caporicci², Ze Yang¹, Matthew Joseph Meiners⁴, Marcus Adrian Cheek⁴, Sarah Ann Howard⁴, Lichao Zhang⁵, Joshua Eric Elias⁵, Michael P Kim⁶, Anirban Maitra⁷, Huamin Wang⁸, Michael Cory Bassik⁹, Michael-Christopher Keogh⁴, Julien Sage¹⁰, Or Gozani¹¹, Pawel K Mazur¹²

Affiliations

¹ Department of Biology, Stanford University, Stanford, CA 94305, USA.
² Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
⁴ EpiCypher Inc., Durham, NC 27709, USA.
⁵ Chan Zuckenberg Biohub, Stanford, CA 94305, USA.
⁶ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁰ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: ogozani@stanford.edu.
¹² Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: pkmazur@mdanderson.org.

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.

Keywords: KRAS; MEK inhibition; RAS signaling; SETD5; lysine methylation; pancreatic cancer; protein methylation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

Chromatin
Histocompatibility Antigens
Protein Kinase Inhibitors
Pyridones
Pyrimidinones
Small Molecule Libraries
trametinib
Methyltransferases
SETD5 protein, human
EHMT2 protein, human
Histone-Lysine N-Methyltransferase
MAP2K2 protein, human
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP2K1 protein, human
Histone Deacetylases
histone deacetylase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding