Cargando…

Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer

Comprehensive characterization of the genomic landscape of epidermal growth factor receptor (EGFR)-mutated lung cancers have identified patterns of secondary mutations beyond the primary oncogenic EGFR mutation. These include concurrent pathogenic alterations affecting p53 (60–65%), RTKs (5–10%), PI...

Descripción completa

Detalles Bibliográficos
Autores principales: Gini, Beatrice, Thomas, Nicholas, Blakely, Collin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330397/
https://www.ncbi.nlm.nih.gov/pubmed/32642201
http://dx.doi.org/10.21037/jtd.2020.03.78
_version_ 1783553112802328576
author Gini, Beatrice
Thomas, Nicholas
Blakely, Collin M.
author_facet Gini, Beatrice
Thomas, Nicholas
Blakely, Collin M.
author_sort Gini, Beatrice
collection PubMed
description Comprehensive characterization of the genomic landscape of epidermal growth factor receptor (EGFR)-mutated lung cancers have identified patterns of secondary mutations beyond the primary oncogenic EGFR mutation. These include concurrent pathogenic alterations affecting p53 (60–65%), RTKs (5–10%), PIK3CA/KRAS (3–23%), Wnt (5–10%), and cell cycle (7–25%) pathways as well as transcription factors such as MYC and NKX2-1 (10–15%). The majority of these co-occurring alterations were detected or enriched in samples collected from patients at resistance to tyrosine kinase inhibitor (TKI) treatment, indicating a potential functional role in driving resistance to therapy. Of note, these co-occurring tumor genomic alterations are not necessarily mutually exclusive, and evidence suggests that multiple clonal and sub-clonal cancer cell populations can co-exist and contribute to EGFR TKI resistance. Computational tools aimed to classify, track and predict the evolution of cancer clonal populations during therapy are being investigated in pre-clinical models to guide the selection of combination therapy switching strategies that may delay the development of treatment resistance. Here we review the most frequently identified tumor genomic alterations that co-occur with mutated EGFR and the evidence that these alterations effect responsiveness to EGFR TKI treatment.
format Online
Article
Text
id pubmed-7330397
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher AME Publishing Company
record_format MEDLINE/PubMed
spelling pubmed-73303972020-07-07 Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer Gini, Beatrice Thomas, Nicholas Blakely, Collin M. J Thorac Dis Review Article on Mechanisms of Resistance to EGFR-targeted Therapy Comprehensive characterization of the genomic landscape of epidermal growth factor receptor (EGFR)-mutated lung cancers have identified patterns of secondary mutations beyond the primary oncogenic EGFR mutation. These include concurrent pathogenic alterations affecting p53 (60–65%), RTKs (5–10%), PIK3CA/KRAS (3–23%), Wnt (5–10%), and cell cycle (7–25%) pathways as well as transcription factors such as MYC and NKX2-1 (10–15%). The majority of these co-occurring alterations were detected or enriched in samples collected from patients at resistance to tyrosine kinase inhibitor (TKI) treatment, indicating a potential functional role in driving resistance to therapy. Of note, these co-occurring tumor genomic alterations are not necessarily mutually exclusive, and evidence suggests that multiple clonal and sub-clonal cancer cell populations can co-exist and contribute to EGFR TKI resistance. Computational tools aimed to classify, track and predict the evolution of cancer clonal populations during therapy are being investigated in pre-clinical models to guide the selection of combination therapy switching strategies that may delay the development of treatment resistance. Here we review the most frequently identified tumor genomic alterations that co-occur with mutated EGFR and the evidence that these alterations effect responsiveness to EGFR TKI treatment. AME Publishing Company 2020-05 /pmc/articles/PMC7330397/ /pubmed/32642201 http://dx.doi.org/10.21037/jtd.2020.03.78 Text en 2020 Journal of Thoracic Disease. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Review Article on Mechanisms of Resistance to EGFR-targeted Therapy
Gini, Beatrice
Thomas, Nicholas
Blakely, Collin M.
Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer
title Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer
title_full Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer
title_fullStr Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer
title_full_unstemmed Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer
title_short Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer
title_sort impact of concurrent genomic alterations in epidermal growth factor receptor (egfr)-mutated lung cancer
topic Review Article on Mechanisms of Resistance to EGFR-targeted Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330397/
https://www.ncbi.nlm.nih.gov/pubmed/32642201
http://dx.doi.org/10.21037/jtd.2020.03.78
work_keys_str_mv AT ginibeatrice impactofconcurrentgenomicalterationsinepidermalgrowthfactorreceptoregfrmutatedlungcancer
AT thomasnicholas impactofconcurrentgenomicalterationsinepidermalgrowthfactorreceptoregfrmutatedlungcancer
AT blakelycollinm impactofconcurrentgenomicalterationsinepidermalgrowthfactorreceptoregfrmutatedlungcancer