title: NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib.
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.
authors.affiliation: INSERM U908, 59655 Villeneuve d'Ascq, France.|University Lille 1, 59655 Villeneuve d'Ascq, France.|SIRIC OncoLille, 59000 Lille, France.
authors.forename: Léo
authors.initials: L
authors.lastname: Aubert
authors.affiliation: INSERM U908, 59655 Villeneuve d'Ascq, France.|University Lille 1, 59655 Villeneuve d'Ascq, France.|SIRIC OncoLille, 59000 Lille, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Guilbert
authors.affiliation: INSERM U908, 59655 Villeneuve d'Ascq, France.|University Lille 1, 59655 Villeneuve d'Ascq, France.|SIRIC OncoLille, 59000 Lille, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Corbet
authors.affiliation: INSERM U1045, 33607 Pessac, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Génot
authors.affiliation: INSERM U908, 59655 Villeneuve d'Ascq, France.|University Lille 1, 59655 Villeneuve d'Ascq, France.|CNRS UMR 8161, 59000 Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Adriaenssens
authors.affiliation: PLETHA, Institut Pasteur de Lille, 59000 Lille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Chassat
authors.affiliation: INSERM UMR 891, Institut Paoli-Calmettes, 13009 Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: INSERM U1045, 33607 Pessac, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daubon
authors.affiliation: Radiobiologie Cellulaire et Moléculaire, EMR3738 - Equipe 4, Faculté de Médecine Lyon-Sud, 69000 Lyon, France.|Département de Radiothérapie, Institut de Cancérologie Lucien Neuwirth, 42270 Saint Priest en Jarez, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Magné
authors.affiliation: INSERM U908, 59655 Villeneuve d'Ascq, France.|University Lille 1, 59655 Villeneuve d'Ascq, France.|SIRIC OncoLille, 59000 Lille, France.
authors.forename: Xuefen
authors.initials: X
authors.lastname: Le Bourhis
authors.affiliation: INSERM U908, 59655 Villeneuve d'Ascq, France.|University Lille 1, 59655 Villeneuve d'Ascq, France.|SIRIC OncoLille, 59000 Lille, France.
authors.forename: Robert-Alain
authors.initials: RA
authors.lastname: Toillon
mesh_terms: D000818:Animals; D019921:Biotinylation; D002227:Carbazoles / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005663:Furans; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020932:Nerve Growth Factor / Q000378:metabolism*; D011485:Protein Binding; D040901:Proteomics; D034741:RNA, Small Interfering / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497483:CD44 protein, human; D002227:Carbazoles; D005663:Furans; D018960:Hyaluronan Receptors; C502240:NGF protein, human; D034741:RNA, Small Interfering; D020932:Nerve Growth Factor; C119379:lestaurtinib; D020917:Receptor, trkA
keywords: CD44; NGF; TrkA; lestaurtinib; resistance
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