title: Increased CD271 expression by the NF-kB pathway promotes melanoma cell survival and drives acquired resistance to BRAF inhibitor vemurafenib.
abstract: Specific BRAFV600E inhibitors (BRAFi) are highly effective in the treatment of melanoma. However, acquired drug resistances invariably develop after the initial response. Therefore, the identification of new mechanisms of acquired resistance gives important clues towards the development of therapies that could elicit long lasting responses. Here we report that CD271 confers resistance to BRAFi in melanoma cells. The expression of CD271 is increased by BRAFi through a stimulation of tumor necrosis factor-alpha (TNFα) secretion that leads to NF-κB signaling pathway activation. CD271 is upregulated in a subset of BRAFi-resistant melanoma cells. The inhibition of TNFα/NF-κB pathway and CD271 silencing restore the BRAFi sensitivity of resistant melanoma cells. Finally, increase of CD271 expression is validated in BRAFi-resistant xenografts tumors and also in tumors from the patients who relapsed under BRAFi. In summary, these results reveal a novel TNFα/NF-κB/CD271 axis whose activation contributes to the acquisition of resistance to BRAFi and therefore may represent a novel therapeutic target to improve the efficacy of therapy in melanoma.
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France.
authors.forename: Abdelali
authors.initials: A
authors.lastname: Lehraiki
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Cerezo
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Rouaud
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Abbe
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Allegra
authors.affiliation: INSERM, U837, équipe 4 et Faculté de Médecine, Université de Lille II , Lille, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Kluza
authors.affiliation: INSERM, U837, équipe 4 et Faculté de Médecine, Université de Lille II , Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: INSERM, U1065, équipe 4, Centre Méditerranéen de Médecine Moléculaire (C3M) , Nice, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Imbert
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Cheli
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, Nice, France.
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, Nice, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.affiliation: INSERM, U1065, équipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France; Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, Nice, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Rocchi
keywords: CD271; NF-κB; TNFα; melanoma; resistance; vemurafenib