ERBB4 Drives BRAF WT Melanomas

Joelle Woggerman, Undergraduate, Biochemistry

Department of Drug Discovery and Development

Harrison College of Pharmacy

Auburn University

10/28/2022

The ERBB Family of Receptor Tyrosine Kinases

Lucas, L. M., et al. Pharmacological Reviews (2022)

ERBB family receptors participate in ligand-mediated dimerization

Lucas, L. M., et al. Pharmacological Reviews (2022)

ERBB family receptors bind numerous ligands and can homodimerize or heterodimerize

Lucas, L. M., et al. Pharmacological Reviews (2022)

EGFR and ERBB2 are well established oncogenes in various cancer types

ERBB4 homodimers have tumor suppressor activity

DU-145

Williams, E., Cancer Letters (2003)

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MIA-PaCa-2

Mill, C., Exp Cell Res (2011)

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MCF7

Mill, C., Genes and Cancer, 2008

Homodimerization

ERBB4 heterodimers have oncogenic activity

MIA-PaCa-2

Mill, C., Exp Cell Res (2011)

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MCF7

Mill, C., Genes and Cancer, 2008

Differences in sites of ERBB4 tyrosine phosphorylation and coupling to downstream signaling effectors may account for the functional differences between ERBB4 homodimers and heterodimers

Lucas, L. M., et al. Pharmacological Reviews (2022)

Identifying the need in the treatment of melanoma

• Greater than 85% of melanomas exhibit elevated RAS/RAF/MAPK pathway signaling
• ~50% of melanomas harbor a BRAF V600 mutation
• ~40% of melanoma harbor a RAS or NF1 mutation resulting in increased RAS activity
• BRAF V600 mutant positive patients undergo combination therapy with BRAF and MEK inhibitors
• RAS and NF1 mutant patients have limited targeted therapeutic options
• Triple wild-type melanomas are rare, have no available targeted therapeutic, and there’s a lack of suitable cell culture model systems

There remains a significant need for targeted treatment of BRAF WT melanomas

437 cases of BRAF V600 and BRAF WT melanoma from the Cancer Genome Atlas – Skin Cutaneous Melanoma dataset (TCGA-SKCM)

In BRAF WT melanomas, ERBB4 expression is elevated in cases that contain a RAS/NF1 mutation

Melanoma Cell Culture Model System

Non-Melanoma Control Cell Line:

• C127 Cell Line

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Melanoma Cell Lines:

• MEL-JUSO
• MeWo
• IPC-298
• SK-MEL-2
• HMCB
• COLO-792

Ectopic WT ERBB4 expression is sufficient for clonogenic proliferation in multiple BRAF WT melanoma cell lines

The ERBB4 K751M dominant negative mutant suggests that ERBB4 function is necessary for clonogenic proliferation in multiple BRAF WT melanoma cell lines

The ERBB4 K751M dominant negative mutant suggests that ERBB4 function is necessary for anchorage independence of BRAF WT MEL-JUSO cells

Future Questions

• What is the role of ERBB4-EGFR and ERBB4-ERBB2 heterodimers in ERBB4-dependent BRAF WT melanoma cell lines?
• How do ERBB4 mutants found in BRAF WT melanomas affect BRAF WT melanoma cell lines?
• Do all BRAF WT melanoma cell lines respond equally to individual ERBB4 mutants?
• Might differences in ERBB4-EGFR or ERBB4-ERBB2 heterodimerization account for this specificity?
• Are ERBB4-dependent BRAF WT melanoma cell lines also sensitive to PI3 kinase inhibitors?
• Are ERBB4-dependent BRAF WT melanoma cell lines also dependent on endogenous ERBB4 ligands?

Acknowledgements

Primary Investigator:

Dr. David Riese II

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Lead Graduate Researcher:

Lauren Lucas

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Department of Drug Discovery and Development

References

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