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

Kieren D. Marini; David R. Croucher; Rachael A. McCloy; Vijesh Vaghjiani; Alvaro Gonzalez-Rajal; Jordan F. Hastings; Venessa Chin; Anette Szczepny; Kaja Kostyrko; Cesar Marquez; W. Samantha; N. Jayasekara; Muhammad Alamgeer; Vishal Boolell; Jeremy Z.R. Han; Todd Waugh; Hong Ching Lee; Samantha R. Oakes; Beena Kumar; Craig A. Harrison; Mark P. Hedger; Nirmal Lorensuhewa; Badia Kita; Ross Barrow; Bruce W. Robinson; David M. De Kretser; Jianmin Wu; Vinod Ganju; E. Alejandro Sweet-Cordero; Andrew Burgess; Luciano G. Martelotto; Fernando J. Rossello; Jason E. Cain; D. Neil Watkins

doi:10.1126/scitranslmed.aat3504

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

Kieren D. Marini, David R. Croucher, Rachael A. McCloy, Vijesh Vaghjiani, Alvaro Gonzalez-Rajal, Jordan F. Hastings, Venessa Chin, Anette Szczepny, Kaja Kostyrko, Cesar Marquez, W. Samantha, N. Jayasekara, Muhammad Alamgeer, Vishal Boolell, Jeremy Z.R. Han, Todd Waugh, Hong Ching Lee, Samantha R. Oakes, Beena Kumar, Craig A. HarrisonMark P. Hedger, Nirmal Lorensuhewa, Badia Kita, Ross Barrow, Bruce W. Robinson, David M. De Kretser, Jianmin Wu, Vinod Ganju, E. Alejandro Sweet-Cordero, Andrew Burgess, Luciano G. Martelotto, Fernando J. Rossello, Jason E. Cain, D. Neil Watkins

UWA Medical School

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

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- (TGF) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGF-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 language	English
Article number	eaat3504
Journal	Science Translational Medicine
Volume	10
Issue number	451
DOIs	https://doi.org/10.1126/scitranslmed.aat3504
Publication status	Published - 25 Jul 2018

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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., Samantha, W., Jayasekara, N., Alamgeer, M., Boolell, V., Han, J. Z. R., Waugh, T., Lee, H. C., Oakes, S. R., Kumar, B., ... Neil Watkins, D. (2018). Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy. Science Translational Medicine, 10(451), Article eaat3504. https://doi.org/10.1126/scitranslmed.aat3504

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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- (TGF) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGF-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 = "Marini, {Kieren D.} and Croucher, {David R.} and McCloy, {Rachael A.} and Vijesh Vaghjiani and Alvaro Gonzalez-Rajal and Hastings, {Jordan F.} and Venessa Chin and Anette Szczepny and Kaja Kostyrko and Cesar Marquez and W. Samantha and N. Jayasekara 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 A.} and Hedger, {Mark P.} and Nirmal Lorensuhewa and Badia Kita and Ross Barrow and Robinson, {Bruce W.} and {De Kretser}, {David M.} and Jianmin Wu and Vinod Ganju and {Alejandro Sweet-Cordero}, E. and Andrew Burgess and Martelotto, {Luciano G.} and Rossello, {Fernando J.} and Cain, {Jason E.} and {Neil Watkins}, D.",

year = "2018",

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doi = "10.1126/scitranslmed.aat3504",

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Marini, KD, Croucher, DR, McCloy, RA, Vaghjiani, V, Gonzalez-Rajal, A, Hastings, JF, Chin, V, Szczepny, A, Kostyrko, K, Marquez, C, Samantha, W, Jayasekara, N, Alamgeer, M, Boolell, V, Han, JZR, Waugh, T, Lee, HC, Oakes, SR, Kumar, B, Harrison, CA, Hedger, MP, Lorensuhewa, N, Kita, B, Barrow, R, Robinson, BW, De Kretser, DM, Wu, J, Ganju, V, Alejandro Sweet-Cordero, E, Burgess, A, Martelotto, LG, Rossello, FJ, Cain, JE & Neil Watkins, D 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

TY - JOUR

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

AU - Marini, Kieren D.

AU - Croucher, David R.

AU - McCloy, Rachael A.

AU - Vaghjiani, Vijesh

AU - Gonzalez-Rajal, Alvaro

AU - Hastings, Jordan F.

AU - Chin, Venessa

AU - Szczepny, Anette

AU - Kostyrko, Kaja

AU - Marquez, Cesar

AU - Samantha, W.

AU - Jayasekara, N.

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 A.

AU - Hedger, Mark P.

AU - Lorensuhewa, Nirmal

AU - Kita, Badia

AU - Barrow, Ross

AU - Robinson, Bruce W.

AU - De Kretser, David M.

AU - Wu, Jianmin

AU - Ganju, Vinod

AU - Alejandro Sweet-Cordero, E.

AU - Burgess, Andrew

AU - Martelotto, Luciano G.

AU - Rossello, Fernando J.

AU - Cain, Jason E.

AU - Neil Watkins, D.

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- (TGF) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGF-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- (TGF) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGF-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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U2 - 10.1126/scitranslmed.aat3504

DO - 10.1126/scitranslmed.aat3504

M3 - Article

C2 - 30045976

AN - SCOPUS:85050729874

SN - 1946-6234

VL - 10

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 451

M1 - eaat3504

ER -

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

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