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

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) superf...

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Bibliographic Details
Published in:Science translational medicine 2018-07, Vol.10 (451)
Main Authors: Marini, Kieren D, Croucher, David R, McCloy, Rachael A, Vaghjiani, Vijesh, Gonzalez-Rajal, Alvaro, Hastings, Jordan F, Chin, Venessa, Szczepny, Anette, Kostyrko, Kaja, Marquez, Cesar, Jayasekara, W Samantha N, Alamgeer, Muhammad, Boolell, Vishal, Han, Jeremy Z R, Waugh, Todd, Lee, Hong Ching, Oakes, Samantha R, Kumar, Beena, Harrison, Craig A, Hedger, Mark P, Lorensuhewa, Nirmal, Kita, Badia, Barrow, Ross, Robinson, Bruce W, de Kretser, David M, Wu, Jianmin, Ganju, Vinod, Sweet-Cordero, E Alejandro, Burgess, Andrew, Martelotto, Luciano G, Rossello, Fernando J, Cain, Jason E, Watkins, D Neil
Format: Article
Language:English
Subjects:
Activin
Adenocarcinoma
Cell death
Chemotherapy
Cisplatin
Follistatin
Genomes
Growth differentiation factor 11
Lung cancer
Platinum
RNA-mediated interference
Smad protein
TAK1 protein
Therapeutic applications
Transcription factors
Transforming growth factor-b
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Summary: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.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.aat3504