title: PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation.
abstract: Control of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance. PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sabbatino
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
authors.forename: David
authors.initials: D
authors.lastname: Pepin
authors.forename: Giosue
authors.initials: G
authors.lastname: Scognamiglio
authors.forename: Stefano
authors.initials: S
authors.lastname: Pepe
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000737:chemistry / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000077210:Sunitinib; D015854:Up-Regulation; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D013449:Sulfonamides; C561435:sonidegib; D000077484:Vemurafenib; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C577197:crenolanib; D000077210:Sunitinib
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