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https://repository.monashhealth.org/monashhealthjspui/handle/1/36886| Title: | Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy. | Authors: | Boolell V.;Vaghjiani V.;Gonzalez-Rajal A.;Hastings J.F.;Chin V.;Szczepny A.;Kostyrko K.;Marquez C.;Samantha W.;Jayasekara N.;McCloy R.A.;Han J.Z.R.;Waugh T.;Lee H.C.;Oakes S.R.;Harrison C.A.;Hedger M.P.;Lorensuhewa N.;Kita B.;Barrow R.;Robinson B.W.;De Kretser D.M.;Wu J.;Ganju V.;Alejandro Sweet-Cordero E.;Burgess A.;Martelotto L.G.;Rossello F.J.;Cain J.E.;Neil Watkins D.;Kumar B. ;Alamgeer M. ;Marini K.D.;Croucher D.R. | Institution: | (Marini, Vaghjiani, Szczepny, Jayasekara, Alamgeer, Boolell, Waugh, Harrison, Hedger, De Kretser, Ganju, Cain) Hudson Institute of Medical Research, Clayton, VIC 3168, Australia (Marini, Alamgeer, Harrison, Hedger, De Kretser, Ganju, Martelotto) Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia (Croucher, McCloy, Gonzalez-Rajal, Hastings, Chin, Han, Lee, Oakes, Wu, Burgess, Neil Watkins) Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia (Croucher, Oakes, Wu, Neil Watkins) St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, NSW 2010, Australia (Croucher) School of Medicine, University College Dublin, Belfield, Dublin D04 V1W8, Ireland (Chin) Department of Medical Oncology, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia (Kostyrko, Marquez, Alejandro Sweet-Cordero) Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, United States (Alamgeer, Boolell) Department of Medical Oncology, Monash Medical Centre, East Bentleigh, VIC 3165, Australia (Kumar) Department of Pathology, Monash Medical Centre, Clayton, VIC 3168, Australia (Lorensuhewa, Kita, Barrow, De Kretser) Paranta Biosciences Limited, Melbourne, VIC 3004, Australia (Robinson) School of Medicine and Pharmacology, Queen Elizabeth II Medical Centre Unit, University of Western Australia, Crawley, WA 6009, Australia (Wu) Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China (Wu) Center for Cancer Bioinformatics, Peking University Cancer Hospital and Institute, Hai-Dian District, Beijing 100142, China (Burgess) ANZAC Research Institute, Concord, NSW 2139, Australia (Martelotto) Center for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC 3000, Australia (Rossello) Australian Regenerative Medicine Institute, Clayton, VIC 3800, Australia (Rossello) Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia (Neil Watkins) Department of Thoracic Medicine, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia | Issue Date: | 7-Aug-2018 | Copyright year: | 2018 | Publisher: | American Association for the Advancement of Science | Place of publication: | United States | Publication information: | Science Translational Medicine. 10 (451) (no pagination), 2018. Article Number: eaat3504. Date of Publication: 25 Jul 2018. | Journal: | Science Translational Medicine | Abstract: | Resistance to platinum chemotherapy is a long-standing problem in the management of lung adenocarcinoma. Using a whole-genome synthetic lethal RNA interference screen, we identified activin signaling as a critical mediator of innate platinum resistance. The transforming growth factor- (TGF) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGF-activated kinase 1 (TAK1), rather than through the SMAD family of transcription factors. Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance. Consistent with the role of activin signaling in acute renal injury, both therapeutic interventions attenuated acute cisplatin-induced nephrotoxicity, its major dose-limiting side effect. This cancer-specific enhancement of platinum-induced cell death has the potential to dramatically improve the safety and efficacy of chemotherapy in lung cancer patients.Copyright © 2018 The Authors, some rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1126/scitranslmed.aat3504 | PubMed URL: | 30045976 [http://www.ncbi.nlm.nih.gov/pubmed/?term=30045976] | ISSN: | 1946-6234 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/36886 | Type: | Article |
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