| Literature DB >> 30045976 |
Kieren D Marini1,2, David R Croucher3,4,5, Rachael A McCloy3, Vijesh Vaghjiani1, Alvaro Gonzalez-Rajal3, Jordan F Hastings3, Venessa Chin3,6, Anette Szczepny1, Kaja Kostyrko7, Cesar Marquez7, W Samantha N Jayasekara1, Muhammad Alamgeer1,2,8, Vishal Boolell1,8, Jeremy Z R Han3, Todd Waugh1, Hong Ching Lee3, Samantha R Oakes3,4, Beena Kumar9, Craig A Harrison1,2, Mark P Hedger1,2, Nirmal Lorensuhewa10, Badia Kita10, Ross Barrow10, Bruce W Robinson11, David M de Kretser1,2,10, Jianmin Wu3,4,12,13, Vinod Ganju1,2, E Alejandro Sweet-Cordero7, Andrew Burgess3,14, Luciano G Martelotto2,15, Fernando J Rossello16,17, Jason E Cain18, D Neil Watkins19,4,20.
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.Entities:
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Year: 2018 PMID： 30045976 DOI： 10.1126/scitranslmed.aat3504
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956