Oncotarget

Research Papers:

NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib

Léo Aubert _, Matthieu Guilbert, Cyril Corbet, Elisabeth Génot, Eric Adriaenssens, Thierry Chassat, François Bertucci, Thomas Daubon, Nicolas Magné, Xuefen Le Bourhis and Robert-Alain Toillon

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Oncotarget. 2015; 6:9807-9819. https://doi.org/10.18632/oncotarget.3227

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Abstract

Léo Aubert1,2,3,*, Matthieu Guilbert1,2,3,*, Cyril Corbet1,2,3, Elisabeth Génot4, Eric Adriaenssens1,2,5, Thierry Chassat6, François Bertucci7, Thomas Daubon4, Nicolas Magné8,9, Xuefen Le Bourhis1,2,3,#, Robert-Alain Toillon1,2,3,#

1INSERM U908, 59655 Villeneuve d’Ascq, France

2University Lille 1, 59655 Villeneuve d’Ascq, France

3SIRIC OncoLille, 59000 Lille, France

4INSERM U1045, 33607 Pessac, France

5CNRS UMR 8161, 59000 Lille, France

6PLETHA, Institut Pasteur de Lille, 59000 Lille, France

7INSERM UMR 891, Institut Paoli-Calmettes, 13009 Marseille, France

8Radiobiologie Cellulaire et Moléculaire, EMR3738 - Equipe 4, Faculté de Médecine Lyon-Sud, 69000 Lyon, France

9Département de Radiothérapie, Institut de Cancérologie Lucien Neuwirth, 42270 Saint Priest en Jarez, France

*These authors have contributed equally to this work

#The two last authors have contributed equally to this work

Correspondence to:

Robert-Alain Toillon, e-mail: [email protected]

Keywords: CD44, NGF, TrkA, lestaurtinib, resistance

Received: October 17, 2014     Accepted: January 27, 2015     Published: March 25, 2015

ABSTRACT

There is accumulating evidence that TrkA and its ligand Nerve Growth Factor (NGF) are involved in cancer development. Staurosporine derivatives such as K252a and lestaurtinib have been developed to block TrkA kinase signaling, but no clinical trial has fully demonstrated their therapeutic efficacy. Therapeutic failures are likely due to the existence of intrinsic signaling pathways in cancer cells that impede or bypass the effects of TrkA tyrosine kinase inhibitors. To verify this hypothesis, we combined different approaches including mass spectrometry proteomics, co-immunoprecipitation and proximity ligation assays. We found that NGF treatment induced CD44 binding to TrkA at the plasma membrane and subsequent activation of the p115RhoGEF/RhoA/ROCK1 pathway to stimulate breast cancer cell invasion. The NGF-induced CD44 signaling was independent of TrkA kinase activity. Moreover, both TrkA tyrosine kinase inhibition with lestaurtinib and CD44 silencing with siRNA inhibited cell growth in vitro as well as tumor development in mouse xenograft model; combined treatment significantly enhanced the antineoplastic effects of either treatment alone. Altogether, our results demonstrate that NGF-induced tyrosine kinase independent TrkA signaling through CD44 was sufficient to maintain tumor aggressiveness. Our findings provide an alternative mechanism of cancer resistance to lestaurtinib and indicate that dual inhibition of CD44 and TrkA tyrosine kinase activity may represent a novel therapeutic strategy.


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