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Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2

We previously reported CD63-BCAR4 fusion as a novel oncogene that significantly enhanced cell migration and metastasis in lung cancer. To identify effective inhibitors of metastatic activity induced by BCAR4 fusion, we screened a drug library of 381 FDA-approved compounds. The effect of drugs on cel...

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Autores principales: Bae, Kieun, Kim, Jin Hee, Lee, Ja Young, Kong, Sun-Young, Kim, Yun-Hee, Kim, Sunshin, Yoon, Kyong-Ah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9445485/
https://www.ncbi.nlm.nih.gov/pubmed/36081848
http://dx.doi.org/10.3389/fmolb.2022.952651
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author Bae, Kieun
Kim, Jin Hee
Lee, Ja Young
Kong, Sun-Young
Kim, Yun-Hee
Kim, Sunshin
Yoon, Kyong-Ah
author_facet Bae, Kieun
Kim, Jin Hee
Lee, Ja Young
Kong, Sun-Young
Kim, Yun-Hee
Kim, Sunshin
Yoon, Kyong-Ah
author_sort Bae, Kieun
collection PubMed
description We previously reported CD63-BCAR4 fusion as a novel oncogene that significantly enhanced cell migration and metastasis in lung cancer. To identify effective inhibitors of metastatic activity induced by BCAR4 fusion, we screened a drug library of 381 FDA-approved compounds. The effect of drugs on cell migration was evaluated by monitoring wound healing. Drugs that decreased the cellular mobility of fusion-overexpressing cells compared with that of control cells were selected as candidates. Library screening revealed that erlotinib, canertinib, and lapatinib demonstrated inhibitory effects on cell migration. Activation of the EGFR signaling pathway was detected after ectopic expression of CD63-BCAR4 in normal bronchial epithelial cells, as observed by the increased phosphorylation of tyrosine residues in the EGFR protein. We also confirmed increased levels of the phosphorylated EGFR protein in resected tumors from mice injected with CD63-BCAR4 overexpressing cells. Tyrosine kinase inhibitors (TKIs) of the EGFR family significantly inhibit the migration of BCAR4 fusion-overexpressing cells and induce apoptosis at high concentrations. Among the EGFR family TKIs, canertinib, a dual EGFR/HER2 inhibitor, showed the best inhibitory effect on the migration and viability of BCAR4 fusion-overexpressing cells. We examined the effect of canertinib in vivo using a mouse xenograft model. Oral administration of canertinib to xenografted mice reduced tumor growth induced by the CD63-BCAR4 fusion gene. In addition, canertinib treatment restored E-cadherin expression and reduced the expression of epithelial–mesenchymal transition regulatory factors such as Slug and Snail. Taken together, these results suggest that EGFR/HER2 inhibitors are potential therapeutic options for BCAR4 fusion-harboring lung cancer patients, even in the absence of EGFR mutations.
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spelling pubmed-94454852022-09-07 Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2 Bae, Kieun Kim, Jin Hee Lee, Ja Young Kong, Sun-Young Kim, Yun-Hee Kim, Sunshin Yoon, Kyong-Ah Front Mol Biosci Molecular Biosciences We previously reported CD63-BCAR4 fusion as a novel oncogene that significantly enhanced cell migration and metastasis in lung cancer. To identify effective inhibitors of metastatic activity induced by BCAR4 fusion, we screened a drug library of 381 FDA-approved compounds. The effect of drugs on cell migration was evaluated by monitoring wound healing. Drugs that decreased the cellular mobility of fusion-overexpressing cells compared with that of control cells were selected as candidates. Library screening revealed that erlotinib, canertinib, and lapatinib demonstrated inhibitory effects on cell migration. Activation of the EGFR signaling pathway was detected after ectopic expression of CD63-BCAR4 in normal bronchial epithelial cells, as observed by the increased phosphorylation of tyrosine residues in the EGFR protein. We also confirmed increased levels of the phosphorylated EGFR protein in resected tumors from mice injected with CD63-BCAR4 overexpressing cells. Tyrosine kinase inhibitors (TKIs) of the EGFR family significantly inhibit the migration of BCAR4 fusion-overexpressing cells and induce apoptosis at high concentrations. Among the EGFR family TKIs, canertinib, a dual EGFR/HER2 inhibitor, showed the best inhibitory effect on the migration and viability of BCAR4 fusion-overexpressing cells. We examined the effect of canertinib in vivo using a mouse xenograft model. Oral administration of canertinib to xenografted mice reduced tumor growth induced by the CD63-BCAR4 fusion gene. In addition, canertinib treatment restored E-cadherin expression and reduced the expression of epithelial–mesenchymal transition regulatory factors such as Slug and Snail. Taken together, these results suggest that EGFR/HER2 inhibitors are potential therapeutic options for BCAR4 fusion-harboring lung cancer patients, even in the absence of EGFR mutations. Frontiers Media S.A. 2022-08-23 /pmc/articles/PMC9445485/ /pubmed/36081848 http://dx.doi.org/10.3389/fmolb.2022.952651 Text en Copyright © 2022 Bae, Kim, Lee, Kong, Kim, Kim and Yoon. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Bae, Kieun
Kim, Jin Hee
Lee, Ja Young
Kong, Sun-Young
Kim, Yun-Hee
Kim, Sunshin
Yoon, Kyong-Ah
Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2
title Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2
title_full Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2
title_fullStr Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2
title_full_unstemmed Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2
title_short Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2
title_sort oncogenic fusion of bcar4 activates egfr signaling and is sensitive to dual inhibition of egfr/her2
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9445485/
https://www.ncbi.nlm.nih.gov/pubmed/36081848
http://dx.doi.org/10.3389/fmolb.2022.952651
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