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

Kieren D MariniDavid R CroucherRachael A McCloyVijesh VaghjianiAlvaro Gonzalez RajalJordan F HastingsVenessa T ChinAnette SzczepnyKaja KostyrkoCesar MarquezW Samantha Nilanthi JayasekaraMuhammad AlamgeerVishal BoolellJeremy Z R HanTodd WaughHong Ching LeeSamantha Richelle OakesBeena KumarCraig A HarrisonMark P HedgerNirmal LorensuhewaBadia KitaRoss BarrowBruce W S RobinsonDavid M de KretserJianmin WuVinod GanjuE Alejandro Sweet-CorderoAndrew BurgessLuciano G MartelottoFernando J RosselloJason E CainD Neil Watkins
Published in: Science translational medicine (2019)
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.
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