| Literature DB >> 32442403 |
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.
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.Entities:
Keywords: KRAS; MEK inhibition; RAS signaling; SETD5; lysine methylation; pancreatic cancer; protein methylation
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Year: 2020 PMID： 32442403 PMCID： PMC8187079 DOI： 10.1016/j.ccell.2020.04.014
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743