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Supplementary Figures S1-6 from ErbB3–ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas

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posted on 2023-03-30, 23:06 authored by Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Amel Salhi, Nadège Gaborit, Tingting Zhan, Inna Chervoneva, Jason Roszik, Scott E. Woodman, Michael A. Davies, Yulius Y. Setiady, Iman Osman, Yosef Yarden, Andrew E. Aplin
<p>Supplementary Figures S1-6 Supplemental Fig. S1. ErbB3 and ErbB4 expression in melanoma cell lines. Supplemental Fig. S2. Depletion of NRG1 inhibits ErbB3 downstream signaling and cell growth in WT/WT melanoma cell lines. Supplemental Fig. S3. Depletion of ErbB3 reduces AKT and ERK1/2 phosphorylation. Supplemental Fig. S4. huHER3-8 reduces AKT phosphorylation. Supplemental Fig. S5. Pertuzumab reduces phosphorylation of AKT and ERK1/2 and inhibits cell growth. Supplemental Fig. S6. MEK inhibitors increase pertuzumab efficacy in xenografts.</p>

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    DOI - Is supplement to ErbB3–ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas

ARTICLE ABSTRACT

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro, and xenograft growth in vivo. Pertuzumab also potentiated the effects of MEK inhibitor on WT/WT melanoma growth in vitro and in vivo. These findings demonstrate that targeting ErbB3–ErbB2 signaling in a cohort of WT/WT melanomas leads to tumor growth reduction. Together, these studies support the rationale to target the NRG1–ErbB3–ErbB2 axis as a novel treatment strategy in a subset of cutaneous melanomas. Cancer Res; 75(17); 3554–67. ©2015 AACR.

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    CarcinogenesisSignal transductionCell CycleSignal transduction pathwaysSkin Cancers

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