Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

Oliveres, Helena; Pesántez, David; Maurel, Joan

doi:10.3390/ijms22095019

Cited by 8 publications

(7 citation statements)

References 118 publications

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“…Receptor tyrosine kinases typically stimulate RAS pathway signaling [28][29][30][31][32][33][34]. Hence, we predicted that elevated ERBB4 expression (which is likely to cause elevated ERBB4 signaling) would be inversely correlated with gain-of-function RAS gene mutations or loss-of-function NF1 mutations in BRAF WT melanomas of the TCGA-SKCM dataset.…”

Section: B Elevated Erbb4 Expression Is Correlated With Ras or Nf1 Mu...mentioning

confidence: 99%

ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

Lucas

Cullum

Dwivedi

et al. 2022

Preprint

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Metastatic skin cutaneous melanomas remain a significant clinical problem. In particular, those melanomas that do not contain a gain-of-function BRAF allele remain challenging to treat because of the paucity of targets for therapeutic intervention. Thus, here we investigate the role of the ERBB4 receptor tyrosine kinase in skin cutaneous melanomas that contain wild-type BRAF alleles (“BRAF WT melanomas”). We have performed in silico analyses of a public repository (The Cancer Genome Atlas - TCGA) of skin cutaneous melanoma gene expression and mutation data (TCGA-SKCM data set). These analyses demonstrate that ERBB4 overexpression strongly correlates with RAS gene or NF1 mutations that stimulate RAS signaling. Thus, these results have led us to hypothesize that elevated ERBB4 signaling promotes PI3K signaling, which cooperates with elevated RAS signaling to drive BRAF WT melanomas. We have tested this hypothesis using commercially available BRAF WT melanoma cell lines. Overexpression of wild-type ERBB4 stimulates clonogenic proliferation of the MEL-JUSO, MEWO, and IPC-298 BRAF WT melanoma cell lines. Moreover, overexpression of a dominant-negative ERBB4 (K751M) mutant inhibits clonogenic proliferation of the MEL-JUSO and MEWO cell lines. We discuss how these results may impact strategies for treating metastatic BRAF WT skin cutaneous melanomas.

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Section: B Elevated Erbb4 Expression Is Correlated With Ras or Nf1 Mu...mentioning

confidence: 99%

ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

Lucas

Cullum

Dwivedi

et al. 2022

Preprint

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“…Insulin-like peptides (ILPs), which include IGF-1, IGF-2, insulin, and seven relaxin-related peptides sharing the same basal fold in humans, are evolutionary conserved factors that play a central role in the regulation of energy metabolism, cell growth and proliferation, and neurotransmission ( 7 , 8 , 17 ).…”

Section: Tumor Microenvironment and Insulin-like Peptidesmentioning

confidence: 99%

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

Kamdje¹,

Etet

Kipanyula

et al. 2022

Front. Endocrinol.

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The tumor microenvironment fuels tumorigenesis and induces the development of resistance to anticancer drugs. A growing number of reports support that the tumor microenvironment mediates these deleterious effects partly by overexpressing insulin-like growth factor 1 (IGF-1). IGF-1 is known for its role to support cancer progression and metastasis through the promotion of neovascularization in transforming tissues, and the promotion of the proliferation, maintenance and migration of malignant cells. Anti-IGF therapies showed potent anticancer effects and the ability to suppress cancer resistance to various chemotherapy drugs in in vivo and in vitro preclinical studies. However, high toxicity and resistance to these agents are increasingly being reported in clinical trials. We review data supporting the notion that tumor microenvironment mediates tumorigenesis partly through IGF-1 signaling pathway. We also discuss the therapeutic potential of IGF-1 receptor targeting, with special emphasis on the ability of IGF-R silencing to overcome chemotherapy drug resistance, as well as the challenges for clinical use of anti-IGF-1R therapies.

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“…Receptor tyrosine kinases typically stimulate RAS pathway signaling [37][38][39][40][41][42][43]. Hence, in the BRAF WT melanomas of the TCGA-SKCM dataset, we predicted that cases that contain an ERBB4 missense mutation would be less likely to contain a nonsynonymous mutation in a RAS gene or NF1.…”

Section: Erbb4 Missense Mutants Are Significantly More Common In Tcga...mentioning

confidence: 99%

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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Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

Cited by 8 publications

References 118 publications

ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

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

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