Journal article
Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy
KD Marini, DR Croucher, RA McCloy, V Vaghjiani, A Gonzalez-Rajal, JF Hastings, V Chin, A Szczepny, K Kostyrko, C Marquez, W Samantha, N Jayasekara, M Alamgeer, V Boolell, JZR Han, T Waugh, HC Lee, SR Oakes, B Kumar, CA Harrison Show all
Science Translational Medicine | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2018
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 signalin..
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Awarded by Victorian Cancer Agency
Awarded by Cancer Council NSW
Awarded by National Health and Medical Research Council of Australia
Funding Acknowledgements
This work was supported by the Victorian Cancer Agency (TS10-01), the Cancer Council NSW (RG15-20), the St. Vincent's Clinic Foundation, the Hudson Institute of Medical Research, Paranta Biosciences Limited, the National Health and Medical Research Council of Australia (GNT100120 and GNT546107), the Petre Foundation, and the Victorian Government' Operational Infrastructure Support Program. The contents of this manuscript are solely the responsibility of the participating institutions and individual authors and do not reflect the views of these funding agencies.