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 Hedger & 13 others Nirmal 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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Article numbereaat3504
Number of pages13
JournalScience Translational Medicine
Volume10
Issue number451
DOIs
Publication statusPublished - 25 Jul 2018

Cite this

Marini, Kieren ; Croucher, David R ; McCloy, Rachael A ; Vaghjiani, Vijesh ; Gonzalez-Rajal, Alvaro ; Hastings, Jordan F. ; Chin, Venessa T. ; Szczepny, Anette ; Kostyrko, Kaja ; Marquez, Cesar ; Jayasekara, Walimuni Samantha Nilanthi ; Alamgeer, Muhammad ; Boolell, Vishal ; Han, Jeremy Z. R. ; Waugh, Todd ; Lee, Hong Ching ; Oakes, Samantha R ; Kumar, Beena ; Harrison, Craig Anthony ; Hedger, Mark Peter ; Lorensuhewa, Nirmal ; Kita, Badia ; arrow, Ross B ; Robinson, Bruce W S ; de Kretser, David Morritz ; Wu, Jianmin ; Ganju, Vinod ; Sweet-Cordero, E. Alejandro ; Burgess, Andrew ; Martelotto, Luciano Gaston ; Rossello, Fernando Jaime ; Cain, Jason ; Watkins, David Neil. / Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy. In: Science Translational Medicine. 2018 ; Vol. 10, No. 451.
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title = "Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy",
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.",
author = "Kieren Marini and Croucher, {David R} and McCloy, {Rachael A} and Vijesh Vaghjiani and Alvaro Gonzalez-Rajal and Hastings, {Jordan F.} and Chin, {Venessa T.} and Anette Szczepny and Kaja Kostyrko and Cesar Marquez and Jayasekara, {Walimuni Samantha Nilanthi} and Muhammad Alamgeer and Vishal Boolell and Han, {Jeremy Z. R.} and Todd Waugh and Lee, {Hong Ching} and Oakes, {Samantha R} and Beena Kumar and Harrison, {Craig Anthony} and Hedger, {Mark Peter} and Nirmal Lorensuhewa and Badia Kita and arrow, {Ross B} and Robinson, {Bruce W S} and {de Kretser}, {David Morritz} and Jianmin Wu and Vinod Ganju and Sweet-Cordero, {E. Alejandro} and Andrew Burgess and Martelotto, {Luciano Gaston} and Rossello, {Fernando Jaime} and Jason Cain and Watkins, {David Neil}",
year = "2018",
month = "7",
day = "25",
doi = "10.1126/scitranslmed.aat3504",
language = "English",
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journal = "Science Translational Medicine",
issn = "1946-6234",
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Marini, K, Croucher, DR, McCloy, RA, Vaghjiani, V, Gonzalez-Rajal, A, Hastings, JF, Chin, VT, Szczepny, A, Kostyrko, K, Marquez, C, Jayasekara, WSN, Alamgeer, M, Boolell, V, Han, JZR, Waugh, T, Lee, HC, Oakes, SR, Kumar, B, Harrison, CA, Hedger, MP, Lorensuhewa, N, Kita, B, arrow, RB, Robinson, BWS, de Kretser, DM, Wu, J, Ganju, V, Sweet-Cordero, EA, Burgess, A, Martelotto, LG, Rossello, FJ, Cain, J & Watkins, DN 2018, 'Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy', Science Translational Medicine, vol. 10, no. 451, eaat3504. https://doi.org/10.1126/scitranslmed.aat3504

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

In: Science Translational Medicine, Vol. 10, No. 451, eaat3504, 25.07.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy

AU - Marini, Kieren

AU - Croucher, David R

AU - McCloy, Rachael A

AU - Vaghjiani, Vijesh

AU - Gonzalez-Rajal, Alvaro

AU - Hastings, Jordan F.

AU - Chin, Venessa T.

AU - Szczepny, Anette

AU - Kostyrko, Kaja

AU - Marquez, Cesar

AU - Jayasekara, Walimuni Samantha Nilanthi

AU - Alamgeer, Muhammad

AU - Boolell, Vishal

AU - Han, Jeremy Z. R.

AU - Waugh, Todd

AU - Lee, Hong Ching

AU - Oakes, Samantha R

AU - Kumar, Beena

AU - Harrison, Craig Anthony

AU - Hedger, Mark Peter

AU - Lorensuhewa, Nirmal

AU - Kita, Badia

AU - arrow, Ross B

AU - Robinson, Bruce W S

AU - de Kretser, David Morritz

AU - Wu, Jianmin

AU - Ganju, Vinod

AU - Sweet-Cordero, E. Alejandro

AU - Burgess, Andrew

AU - Martelotto, Luciano Gaston

AU - Rossello, Fernando Jaime

AU - Cain, Jason

AU - Watkins, David Neil

PY - 2018/7/25

Y1 - 2018/7/25

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.aat3504

DO - 10.1126/scitranslmed.aat3504

M3 - Article

VL - 10

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 451

M1 - eaat3504

ER -