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

Cancer cell (2020-05-23)
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
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.

MATERIALS
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