RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors.
| Autor: | Kohlmeyer JL; Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa.; The Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa., Kaemmer CA; The Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa., Pulliam C; Human Toxicology Graduate Program, University of Iowa, Iowa City, Iowa., Maharjan CK; The Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa., Samayoa AM; Post Baccalaureate Research Education Program, University of Iowa, Iowa City, Iowa., Major HJ; Department of Pediatrics, University of Iowa, Iowa City, Iowa., Cornick KE; Department of Pediatrics, University of Iowa, Iowa City, Iowa., Knepper-Adrian V; Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Khanna R; Department of Pharmacology, University of Arizona, Tucson, Arizona., Sieren JC; Department of Radiology, University of Iowa, Iowa City, Iowa., Leidinger MR; Department of Pathology, University of Iowa, Iowa City, Iowa., Meyerholz DK; Department of Pathology, University of Iowa, Iowa City, Iowa., Zamba KD; Department of Biostatistics, University of Iowa, Iowa City, Iowa., Weimer JM; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota., Dodd RD; Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa.; Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Darbro BW; Department of Pediatrics, University of Iowa, Iowa City, Iowa., Tanas MR; Department of Pathology, University of Iowa, Iowa City, Iowa., Quelle DE; Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa. dawn-quelle@uiowa.edu.; The Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa.; Department of Pathology, University of Iowa, Iowa City, Iowa. |
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| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Jun 15; Vol. 26 (12), pp. 2997-3011. Date of Electronic Publication: 2020 Feb 21. |
| DOI: | 10.1158/1078-0432.CCR-19-2706 |
| Abstrakt: | Purpose: Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss of CDK-inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs. Experimental Design: We examined patient-matched MPNSTs and precursor lesions by RNA sequencing (RNA-Seq) and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor-suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors. Results: RABL6A was dramatically upregulated in human MPNSTs compared with precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G Conclusions: RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs. (©2020 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
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