Related Experiment Video
Updated: Apr 6, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas
Claudia Capparelli1, Sheera Rosenbaum1, Lisa D Berman-Booty1
1Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
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.
Insights
For BRAF/NRAS wild-type melanoma, targeting the NRG1-ErbB3-ErbB2 pathway shows promise. Inhibiting this signaling axis reduced tumor growth, offering a new treatment strategy for this patient group.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Limited treatment options exist for BRAF/NRAS wild-type (WT/WT) melanoma.
- A subset of WT/WT melanomas exhibits high basal ErbB3 phosphorylation.
- This high phosphorylation correlates with autocrine neuregulin-1 (NRG1) production.
Purpose of the Study:
- To investigate the role of the NRG1-ErbB3-ErbB2 signaling axis in WT/WT melanoma.
- To evaluate therapeutic strategies targeting this pathway.
Main Methods:
- NRG1 knockdown using siRNA.
- Targeting ErbB3 with siRNAs and monoclonal antibodies (huHER3-8, NG33).
- Inhibiting ErbB2 heterodimerization with pertuzumab.
- Assessing effects on cell viability, phosphorylation (ErbB3, ErbB2, AKT), and tumor growth (in vitro and in vivo).
- Combination therapy with MEK inhibitor.
Main Results:
- NRG1 knockdown reduced WT/WT melanoma cell viability and downstream signaling.
- Direct targeting of ErbB3 or ErbB2 inhibited cell growth and AKT phosphorylation.
- Pertuzumab reduced tumor growth in vivo and potentiated MEK inhibitor efficacy.
- These interventions collectively reduced tumor growth.
Conclusions:
- The NRG1-ErbB3-ErbB2 axis is a critical driver in a subset of WT/WT melanomas.
- Targeting this axis represents a viable therapeutic strategy.
- This pathway inhibition offers a novel treatment approach for specific melanoma patients.
Related Concept Videos
01:07MAPK Signaling Cascades
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38The Ras Gene
Ras is a...
02:23Abnormal Proliferation
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...