2. Academic Validation
  3. Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy

Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy

  • Sci Transl Med. 2018 Jul 25;10(451):eaat3504. doi: 10.1126/scitranslmed.aat3504.
Kieren D Marini 1 2,  David R Croucher 3 4 5,  Rachael A McCloy 3,  Vijesh Vaghjiani 1,  Alvaro Gonzalez-Rajal 3,  Jordan F Hastings 3,  Venessa Chin 3 6,  Anette Szczepny 1,  Kaja Kostyrko 7,  Cesar Marquez 7,  W Samantha N Jayasekara 1,  Muhammad Alamgeer 1 2 8,  Vishal Boolell 1 8,  Jeremy Z R Han 3,  Todd Waugh 1,  Hong Ching Lee 3,  Samantha R Oakes 3 4,  Beena Kumar 9,  Craig A Harrison 1 2,  Mark P Hedger 1 2,  Nirmal Lorensuhewa 10,  Badia Kita 10,  Ross Barrow 10,  Bruce W Robinson 11,  David M de Kretser 1 2 10,  Jianmin Wu 3 4 12 13,  Vinod Ganju 1 2,  E Alejandro Sweet-Cordero 7,  Andrew Burgess 3 14,  Luciano G Martelotto 2 15,  Fernando J Rossello 16 17,  Jason E Cain 18,  D Neil Watkins 19 4 20
Affiliations

Affiliations

  • 1 Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
  • 2 Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3800, Australia.
  • 3 The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
  • 4 St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, New South Wales 2010, Australia.
  • 5 School of Medicine, University College Dublin, Belfield, Dublin D04 V1W8, Ireland.
  • 6 Department of Medical Oncology, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
  • 7 Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA.
  • 8 Department of Medical Oncology, Monash Medical Centre, East Bentleigh, Victoria 3165, Australia.
  • 9 Department of Pathology, Monash Medical Centre, Clayton, Victoria 3168, Australia.
  • 10 Paranta Biosciences Limited, Melbourne, Victoria 3004, Australia.
  • 11 School of Medicine and Pharmacology, Queen Elizabeth II Medical Centre Unit, University of Western Australia, Crawley, Western Australia 6009, Australia.
  • 12 Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China.
  • 13 Center for Cancer Bioinformatics, Peking University Cancer Hospital and Institute, Hai-Dian District, Beijing 100142, China.
  • 14 ANZAC Research Institute, Concord, New South Wales 2139, Australia.
  • 15 Center for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria 3000, Australia.
  • 16 Australian Regenerative Medicine Institute, Clayton, Victoria 3800, Australia.
  • 17 Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
  • 18 Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia. n.watkins@garvan.org.au jason.cain@hudson.org.au.
  • 19 The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia. n.watkins@garvan.org.au jason.cain@hudson.org.au.
  • 20 Department of Thoracic Medicine, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
PMID: 30045976 DOI: 10.1126/scitranslmed.aat3504
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-β (TGFβ) superfamily ligands Activin A and Growth Differentiation Factor 11 (GDF11) mediated resistance via their cognate receptors through TGFβ-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.

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