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

Kieren Marini, David R Croucher, Rachael A McCloy, Vijesh Vaghjiani, Alvaro Gonzalez-Rajal, Jordan F. Hastings, Venessa T. Chin, Anette Szczepny, Kaja Kostyrko, Cesar Marquez, Walimuni Samantha Nilanthi Jayasekara, Muhammad Alamgeer, Vishal Boolell, Jeremy Z. R. Han, Todd Waugh, Hong Ching Lee, Samantha R Oakes, Beena Kumar, Craig Anthony Harrison, Mark Peter HedgerNirmal Lorensuhewa, Badia Kita, Ross B arrow, Bruce W S Robinson, David Morritz de Kretser, Jianmin Wu, Vinod Ganju, E. Alejandro Sweet-Cordero, Andrew Burgess, Luciano Gaston Martelotto, Fernando Jaime Rossello, Jason Cain, David Neil Watkins

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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.
Original languageEnglish
Article numbereaat3504
Number of pages13
JournalScience Translational Medicine
Issue number451
Publication statusPublished - 25 Jul 2018

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