title: Synchronized Targeting of Notch and ERBB Signaling Suppresses Melanoma Tumor Growth through Inhibition of Notch1 and ERBB3.
abstract: Despite significant advances in melanoma therapy, melanoma remains the deadliest form of skin cancer, with a 5-year survival rate of only 15%. Thus, novel treatments are required to address this disease. Notch and ERBB are evolutionarily conserved signaling cascades required for the maintenance of melanocyte precursors. We show that active Notch1 (Notch1(NIC)) and active (phosphorylated) ERBB3 and ERBB2 correlate significantly and are similarly expressed in both mutated and wild-type BRAF melanomas, suggesting these receptors are co-reactivated in melanoma to promote survival. Whereas blocking either pathway triggers modest effects, combining a ?-secretase inhibitor to block Notch activation and a tyrosine kinase inhibitor to inhibit ERBB3/2 elicits synergistic effects, reducing cell viability by 90% and hampering melanoma tumor growth. Specific inhibition of Notch1 and ERBB3 mimics these results, suggesting these are the critical factors triggering melanoma tumor expansion. Notch and ERBB inhibition blunts AKT and NF?B signaling. Constitutive expression of NF?B partially rescues cell death. Blockade of both Notch and ERBB signaling inhibits the slow cycling JARID1B-positive cell population, which is critical for long-term maintenance of melanoma growth. We propose that blocking these pathways is an effective approach to treatment of melanoma patients regardless of whether they carry mutated or wild-type BRAF.
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Keman
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Poki
authors.initials: P
authors.lastname: Wong
authors.affiliation: Departments of Dermatology, Urology, and Medicine, New York University, New York, New York, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Salvaggio
authors.affiliation: Departments of Dermatology, Urology, and Medicine, New York University, New York, New York, USA.
authors.forename: Amel
authors.initials: A
authors.lastname: Salhi
authors.affiliation: Departments of Dermatology, Urology, and Medicine, New York University, New York, New York, USA.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. Electronic address: bxb278@case.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy / Q000379:methods; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D048493:Proto-Oncogene Proteins B-raf