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

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 SageOr Gozani, Pawel K. Mazur

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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.

Original language	English (US)
Pages (from-to)	834-849.e13
Journal	Cancer cell
Volume	37
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2020.04.014
State	Published - Jun 8 2020

Keywords

KRAS
MEK inhibition
RAS signaling
SETD5
lysine methylation
pancreatic cancer
protein methylation

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Small Animal Imaging Facility

Access to Document

10.1016/j.ccell.2020.04.014

Cite this

Wang, Z., Hausmann, S., Lyu, R., Li, T. M., Lofgren, S. M., Flores, N. M., Fuentes, M. E., Caporicci, M., Yang, Z., Meiners, M. J., Cheek, M. A., Howard, S. A., Zhang, L., Elias, J. E., Kim, M. P., Maitra, A., Wang, H., Bassik, M. C., Keogh, M. C., ... Mazur, P. K. (2020). SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy. Cancer cell, 37(6), 834-849.e13. https://doi.org/10.1016/j.ccell.2020.04.014

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 2020, 'SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy', Cancer cell, vol. 37, no. 6, pp. 834-849.e13. https://doi.org/10.1016/j.ccell.2020.04.014

@article{4870ff607b2d4806b0c5e89d89fe874b,

title = "SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy",

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",

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

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jun,

day = "8",

doi = "10.1016/j.ccell.2020.04.014",

language = "English (US)",

volume = "37",

pages = "834--849.e13",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy

AU - Wang, Zhentian

AU - Hausmann, Simone

AU - Lyu, Ruitu

AU - Li, Tie Mei

AU - Lofgren, Shane M.

AU - Flores, Natasha M.

AU - Fuentes, Mary E.

AU - Caporicci, Marcello

AU - Yang, Ze

AU - Meiners, Matthew Joseph

AU - Cheek, Marcus Adrian

AU - Howard, Sarah Ann

AU - Zhang, Lichao

AU - Elias, Joshua Eric

AU - Kim, Michael P.

AU - Maitra, Anirban

AU - Wang, Huamin

AU - Bassik, Michael Cory

AU - Keogh, Michael Christopher

AU - Sage, Julien

AU - Gozani, Or

AU - Mazur, Pawel K.

PY - 2020/6/8

Y1 - 2020/6/8

N2 - 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.

AB - 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.

KW - KRAS

KW - MEK inhibition

KW - RAS signaling

KW - SETD5

KW - lysine methylation

KW - pancreatic cancer

KW - protein methylation

UR - http://www.scopus.com/inward/record.url?scp=85085759753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85085759753&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.04.014

DO - 10.1016/j.ccell.2020.04.014

M3 - Article

C2 - 32442403

AN - SCOPUS:85085759753

SN - 1535-6108

VL - 37

SP - 834-849.e13

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this