ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

Lucas, Lauren M.; Cullum, Richard L.; Dwivedi, Vipasha; Markham, Jessica A.; Woggerman, Joelle N; Kelley, Connor M.; Knerr, Elizabeth L.; Cook, Laura J.; Lucas, H.C.; Waits, Damien S.; Ghosh, Taraswi Mitra; Halanych, Kenneth M.; Gupta, Ram B.; Riese, David J.

doi:10.1101/2022.06.20.22276663

Cited by 2 publications

(10 citation statements)

References 72 publications

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“…Our in silico analysis of ERBB4 mutant alleles is based on The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) dataset (470 cases) [30]. Most of the analyses reported here focus on the 227 cases that possess wild-type (WT) BRAF alleles (“ BRAF WT melanomas”) [8, 30].…”

Section: Resultsmentioning

confidence: 99%

“…The MEL-JUSO, MeWo, and IPC-298 cell lines exhibit endogenous expression of ERBB4 ligands [8]. Thus, ERBB4 mutants could stimulate clonogenic proliferation of these cell lines via a ligand-dependent or ligand-independent mechanism.…”

Section: A Heterologous Model System Can Be Used To Determine Whether...mentioning

confidence: 99%

“…Moreover, the five-year survival of patients with advanced BRAF WT skin cutaneous melanomas treated with immune checkpoint inhibitors is only 48%, less than the 60% experienced by patients with advanced BRAF mutant skin cutaneous melanomas in a parallel study [5]. Hence, our previous work has attempted to address this gap in treatment efficacy by evaluating the ERBB4 receptor tyrosine kinase as a candidate target in BRAF WT skin cutaneous melanomas [8]. ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases (RTKs), which includes the epidermal growth factor receptor (EGFR), ERBB2 (HER2/Neu), and ERBB3 (HER3).…”

Section: Introductionmentioning

confidence: 99%

“…Our previous work has demonstrated that ectopic expression of wild-type ERBB4 stimulates the proliferation of BRAF WT melanoma cell lines and ectopic expression of a dominant-negative (K751M) mutant ERBB4 allele inhibits the proliferation of BRAF WT melanoma cell lines. These data suggest that ERBB4 is a driver of BRAF WT melanomas [8].…”

Section: Introductionmentioning

confidence: 99%

“…We have observed that ERBB4 appears to function as a driver of proliferation in multiple BRAF WT melanoma cell lines [8]. Moreover, ERBB4 mutant alleles, most of which remain largely uncharacterized, have been found in several cancers, including melanomas [9].…”

Section: Introductionmentioning

confidence: 99%

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ERBB4Mutant Alleles Found inBRAFWT Melanomas That Drive the Proliferation of aBRAFWT Melanoma Cell Line

Lucas

Cullum

Markham

et al. 2022

Preprint

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Metastatic skin cutaneous melanomas that contain wild-type BRAF alleles ("BRAF WT melanomas") remain a significant clinical challenge, primarily because of the paucity of targets for therapeutic intervention. In prior work, in silico analyses of The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) dataset suggested that elevated transcription of the gene that encodes the ERBB4 receptor tyrosine kinase may drive BRAF WT melanomas. Moreover, that prior work demonstrated that expression of the wild-type ERBB4 gene (WT ERBB4) stimulates clonogenic proliferation by the MEL-JUSO, MeWo, and IPC-298 human BRAF WT melanoma cell lines. Moreover, expression of a dominant-negative (K751M) ERBB4 mutant (ERBB4 DN) inhibits clonogenic proliferation by the MEL-JUSO and MeWo cell lines. Here we have extended these findings by investigating the role of ERBB4 mutant alleles in BRAF WT melanomas. In silico analyses of the TCGA-SKCM BRAF WT melanoma dataset indicates that ERBB4 missense mutant alleles occur in a non-random manner, suggesting that melanomagenesis selects for the ERBB4 missense mutant alleles. Specifically, ERBB4 missense mutant alleles affect amino acid residues that are weakly correlated with residues conserved in the ERBB3 extracellular domains and the EGFR tyrosine kinase domain. The occurrence of ERBB4 missense mutant alleles in the TCGA-SKCM BRAF WT melanoma dataset is weakly inversely correlated with events that cause ERBB4-independent PI3K pathway signaling and is strongly correlated with events that cause elevated RAS pathway signaling. Thus, the in silico analyses suggest that ERBB4 mutant alleles stimulate PI3K signaling, which cooperates with elevated RAS signaling to drive BRAF WT melanomas. Moreover, the in silico analyses have prioritized the ERBB4 mutant alleles as candidate drivers of BRAF WT melanomas. One of the prioritized ERBB4 mutant alleles (P759L) stimulates greater clonogenic proliferation of MEL- JUSO cells than does WT ERBB4. Thus, our in silico prioritization strategy may effectively identify ERBB4 mutants that drive BRAF WT melanomas. Finally, the results of our in silico analyses suggest that ERBB4-dependent, BRAF WT melanomas may be effectively treated by a combination of a PI3K pathway inhibitor and a RAS pathway inhibitor.

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Section: Resultsmentioning

confidence: 99%

Section: A Heterologous Model System Can Be Used To Determine Whether...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ERBB4Mutant Alleles Found inBRAFWT Melanomas That Drive the Proliferation of aBRAFWT Melanoma Cell Line

Lucas

Cullum

Markham

et al. 2022

Preprint

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Human melanoma cell lines that possess wild-typeBRAFalleles but are dependent onERBB4andERBB2

Dwivedi,

Lucas,

Cooke

et al. 2024

Preprint

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Metastatic skin cutaneous melanomas that contain wild-typeBRAFalleles typically possess an activating mutation in aRASallele or a loss-of-function mutation in anNF1allele ("BRAF-WT&RAS/NF1-mutant melanomas"). Nonetheless, these tumors remain a significant clinical challenge; they are resistant to MEK and BRAF inhibitors, their response to immune checkpoint inhibitors is less robust than the response ofBRAFmutant melanomas to these agents, and additional validated targets for therapeutic intervention have yet to be identified. Previous work from our laboratory has demonstrated thatERBB4is required for the proliferation of the IPC-298, MEL-JUSO, MeWo, and SK-MEL-2 BRAF-WT&RAS/NF1-mutant melanoma cell lines. Surprisingly, the synthetic constitutively dimerized and active Q646CERBB4mutant allele appears to strongly inhibits the proliferation of BRAF-WT&RAS/NF1- mutant melanoma cell lines. Given that we have also previously demonstrated that ERBB4- ERBB2 and ERBB4-EGFR heterodimers are more potent drivers of proliferation than are ERBB4 homodimers, here we begin to test the hypothesis that ERBB4 heterodimers drive the proliferation of BRAF-WT&RAS/NF1-mutant melanoma cell lines. Here we demonstrate that the kinase-deficient (dominant-negative)ERBB2K753A mutant allele inhibits the clonogenic proliferation of the IPC-298, MEL-JUSO, and MeWoERBB4- dependent, BRAF-WT&RAS/NF1-mutant melanoma cell lines. Moreover, the kinase-deficient (dominant-negative)EGFRK721A mutant allele inhibits the clonogenic proliferation of the MeWo cell line, but not the IPC-298 or MEL-JUSO cell lines. Finally, the clonogenic proliferation of the SK-MEL-2ERBB4-dependent, BRAF-WT&RAS/NF1-mutant melanoma cell line is unaffected by theERBB2K753A orEGFRK721A dominant-negative mutant alleles. We discuss these findings in the context of our hypothesis that ERBB4 heterodimers drive the proliferation of BRAF-WT&RAS/NF1-mutant melanoma cell lines.

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ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

Cited by 2 publications

References 72 publications

ERBB4Mutant Alleles Found inBRAFWT Melanomas That Drive the Proliferation of aBRAFWT Melanoma Cell Line

ERBB4Mutant Alleles Found inBRAFWT Melanomas That Drive the Proliferation of aBRAFWT Melanoma Cell Line

Human melanoma cell lines that possess wild-typeBRAFalleles but are dependent onERBB4andERBB2

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