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Oncotarget. 2015;6(12):9807-19.

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

Author information

1
INSERM U908, 59655 Villeneuve d'Ascq, France.
2
University Lille 1, 59655 Villeneuve d'Ascq, France.
3
SIRIC OncoLille, 59000 Lille, France.
4
INSERM U1045, 33607 Pessac, France.
5
CNRS UMR 8161, 59000 Lille, France.
6
PLETHA, Institut Pasteur de Lille, 59000 Lille, France.
7
INSERM UMR 891, Institut Paoli-Calmettes, 13009 Marseille, France.
8
Radiobiologie Cellulaire et Moléculaire, EMR3738 - Equipe 4, Faculté de Médecine Lyon-Sud, 69000 Lyon, France.
9
Département de Radiothérapie, Institut de Cancérologie Lucien Neuwirth, 42270 Saint Priest en Jarez, France.

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.

KEYWORDS:

CD44; NGF; TrkA; lestaurtinib; resistance

PMID:
25840418
PMCID:
PMC4496399
DOI:
10.18632/oncotarget.3227
[Indexed for MEDLINE]
Free PMC Article

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