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
  • 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. [email protected] [email protected].
  • 19. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia. [email protected] [email protected].
  • 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.

Products