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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-beta (TGFbeta) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGFbeta-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.

Type Journal
ISBN 1946-6234
Authors Marini, K. D.; Croucher, D. R.; McCloy, R. A.; Vaghjiani, V.; Gonzalez-Rajal, A.; Hastings, J. F.; Chin, V.; Szczepny, A.; Kostyrko, K.; Marquez, C.; Jayasekara, W. S. N.; Alamgeer, M.; Boolell, V.; Han, J. Z. R.; Waugh, T.; Lee, H. C.; Oakes, S. R.; Kumar, B.; Harrison, C. A.; Hedger, M. P.; Lorensuhewa, N.; Kita, B.; Barrow, R.; Robinson, B. W.; de Kretser, D. M.; Wu, J.; Ganju, V.; Sweet-Cordero, E. A.; Burgess, A.; Martelotto, L. G.; Rossello, F. J.; Cain, J. E.; Watkins, D. N.
Responsible Garvan Author (missing name)
Publisher Name Science Translational Medicine
Published Date 2018-07-25
Published Volume 10
Published Issue 451
Published Pages eaat3504
Status Always Electronic
DOI 10.1126/scitranslmed.aat3504