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SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
- Source :
-
Cancer Cell . Jun2020, Vol. 37 Issue 6, p834-834. 1p. - Publication Year :
- 2020
-
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. • SETD5 is an epigenetic driver of pancreatic cancer resistance to MEK1/2 inhibition • SETD5 has no intrinsic methylation activity on histones, including at H3 lysine 36 • A SETD5 co-repressor complex regulates a network of drug resistance pathways • Co-targeting of MEK1/2 and the SETD5 complex results in sustained tumor inhibition In pancreatic ductal adenocarcinoma (PDAC), a major roadblock in therapies targeting the KRAS-MAPK pathway, such as MEK1/2 inhibition (MEKi), is the rapid emergence of resistance. Wang et al. identify a clinically actionable epigenetic pathway mediated by SETD5 to drive PDAC resistance to MEKi. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15356108
- Volume :
- 37
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Cancer Cell
- Publication Type :
- Academic Journal
- Accession number :
- 143601375
- Full Text :
- https://doi.org/10.1016/j.ccell.2020.04.014