| First Author | Wang Z | Year | 2020 |
| Journal | Cancer Cell | Volume | 37 |
| Issue | 6 | Pages | 834-849.e13 |
| PubMed ID | 32442403 | Mgi Jnum | J:290368 |
| Mgi Id | MGI:6438014 | Doi | 10.1016/j.ccell.2020.04.014 |
| Citation | Wang Z, et al. (2020) SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy. Cancer Cell 37(6):834-849.e13 |
| abstractText | 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. |
