Afatinib resistance in non-small cell lung cancer involves the PI3K/AKT and MAPK/ERK signalling pathways and epithelial-to-mesenchymal transition

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• 作者：Simona Coco ; Anna Truini ; Angela Alama ; Maria Giovanna Dal Bello…
• 关键词：Afatinib ; PI3K/AKT ; MAPK/ERK ; Signalling pathways ; Transition
• 刊名：Targeted Oncology
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：10
• 期：3
• 页码：393-404
• 全文大小：1,294 KB
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• 作者单位：Simona Coco (1)
  Anna Truini (1) (4)
  Angela Alama (1)
  Maria Giovanna Dal Bello (1)
  Roberta Venè (2)
  Anna Garuti (3)
  Enrico Carminati (3)
  Erika Rijavec (1)
  Carlo Genova (1)
  Giulia Barletta (1)
  Claudio Sini (1)
  Alberto Ballestrero (3)
  Francesco Boccardo (4) (5)
  Francesco Grossi (1)
  
  1. Lung Cancer Unit, IRCCS AOU San Martino—IST, L.go R. Benzi 10, 16132, Genoa, Italy
  4. Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università di Genova, V.le Benedetto XV 6, 16132, Genoa, Italy
  2. Immunology Unit, IRCCS AOU San Martino—IST, L.go R. Benzi 10, 16132, Genoa, Italy
  3. Clinica di Medicina Interna ad Indirizzo Oncologico, IRCCS AOU San Martino—IST, L.go R. Benzi 10, 16132, Genoa, Italy
  5. UOC Clinica di Oncologia Medica, IRCCS AOU San Martino—IST, L.go R. Benzi 10, 16132, Genoa, Italy
  
• 刊物主题：Oncology; Biomedicine general;
• 出版者：Springer Paris
• ISSN：1776-260X

文摘

The epidermal growth factor receptor (EGFR) signalling is one of the most deregulated pathways in non-small cell lung cancer (NSCLC). Recently, the development of novel irreversible tyrosine kinase inhibitors (TKI), such as afatinib, has significantly improved the survival of advanced NSCLC patients harbouring activated EGFR mutations. However, treatment with TKI is not always curative due to the development of resistance. In the present study, we investigated the sensitivity to afatinib in two NSCLC EGFR mutated cell lines (NCI-H1650 and NCI-H1975) by expression profile analysis of 92 genes involved in the EGF pathway. Thereafter, the established afatinib resistant clones were evaluated at different biological levels: genomic, by array comparative genomic hybridisation (aCGH) and deep sequencing; transcriptomic, by quantitative polymerase chain reaction (qPCR) and proteomic, by Western blot and immunofluorescence. The baseline gene expression of the two cell lines revealed that NCI-H1650, the less afatinib-responsive cell, showed activation of two main EGFR downstream pathways such as PI3K/AKT and PLCγ/PKC axes. Analysis of the afatinib-resistant cells showed PI3K/AKT and MAPK/ERK pathways activation together with a biological switch from an epithelial-to-mesenchymal phenotype might confer afatinib-resistant properties to this cell line. Our data suggest that the activation of EGFR-dependent downstream pathways might be involved in the occurrence of resistance to afatinib assuming that the EGFR mutational status should not be exclusively considered when selecting TKI treatments. In particular, the epithelial-to-mesenchymal transition might provide a new basis for understanding afatinib resistance. Keywords Afatinib PI3K/AKT MAPK/ERK Signalling pathways Transition