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

Kieren D Marini; David R Croucher; Rachael A McCloy; Vijesh Vaghjiani; Alvaro Gonzalez-Rajal; Jordan F Hastings; Venessa Chin; Anette Szczepny; Kaja Kostyrko; Cesar Marquez; W Samantha N Jayasekara; Muhammad Alamgeer; Vishal Boolell; Jeremy Z R Han; Todd Waugh; Hong Ching Lee; Samantha R Oakes; Beena Kumar; Craig A Harrison; Mark P Hedger; Nirmal Lorensuhewa; Badia Kita; Ross Barrow; Bruce W Robinson; David M de Kretser; Jianmin Wu; Vinod Ganju; E Alejandro Sweet-Cordero; Andrew Burgess; Luciano G Martelotto; Fernando J Rossello; Jason E Cain; D Neil Watkins

doi:10.1126/scitranslmed.aat3504

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.

Authors

Kieren D Marini^{1

2}, David R Croucher^{3

4

5}, Rachael A McCloy³, Vijesh Vaghjiani¹, Alvaro Gonzalez-Rajal³, Jordan F Hastings³, Venessa Chin^{3

6}, Anette Szczepny¹, Kaja Kostyrko⁷, Cesar Marquez⁷, W Samantha N Jayasekara¹, Muhammad Alamgeer^{1

2

8}, Vishal Boolell^{1

8}, Jeremy Z R Han³, Todd Waugh¹, Hong Ching Lee³, Samantha R Oakes^{3

4}, Beena Kumar⁹, Craig A Harrison^{1

2}, Mark P Hedger^{1

2}, Nirmal Lorensuhewa¹⁰, Badia Kita¹⁰, Ross Barrow¹⁰, Bruce W Robinson¹¹, David M de Kretser^{1

2

10}, Jianmin Wu^{3

4

12

13}, Vinod Ganju^{1

2}, E Alejandro Sweet-Cordero⁷, Andrew Burgess^{3

14}, Luciano G Martelotto^{2

15}, Fernando J Rossello^{16

17}, Jason E Cain¹⁸, 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. 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Activins / metabolism*
Adenocarcinoma of Lung / drug therapy*
Animals
Carboplatin / therapeutic use
Cell Line, Tumor
Cell Survival / drug effects
Follistatin / therapeutic use
Humans
Lung Neoplasms / drug therapy*
Male
Mice
Platinum / therapeutic use*
Signal Transduction / drug effects
Xenograft Model Antitumor Assays

Substances

Follistatin
Activins
Platinum
Carboplatin