Gene mutation analysis in EGFR wild type NSCLC responsive to erlotinib: Are there features to guide patient selection?

Paola Ulivi, Angelo Delmonte, Elisa Chiadini, Daniele Calistri, Maximilian Papi, Marita Mariotti, Alberto Verlicchi, Angela Ragazzini, Laura Capelli, Alessandro Gamboni, Maurizio Puccetti, Alessandra Dubini, Marco Angelo Burgio, Claudia Casanova, Lucio Crinò, Dino Amadori, Claudio Dazzi

Research output: Contribution to journalArticle

Abstract

Tyrosine kinase inhibitors (TKIs) are very efficacious in non-small-cell lung cancer (NSCLC) patients harboring activating Epidermal Growth Factor Receptor (EGFR) mutations. However, about 10% of EGFR wild type (wt) patients respond to TKI, with unknown molecular mechanisms of sensitivity. We considered a case series of 34 EGFR wt NSCLC patients responsive to erlotinib after at least one line of therapy. Responsive patients were matched with an equal number of non-responsive EGFR wt patients. A panel of 26 genes, for a total of 214 somatic mutations, was analyzed by MassARRAY® System (Sequenom, San Diego, CA, USA). A 15% KRAS mutation was observed in both groups, with a prevalence of G12C in non-responders (80% vs. 40% in responders). NOTCH1, p53 and EGFR-resistance-related mutations were found more frequently in non-responders, whereas EGFR-sensitizing mutations and alterations in genes involved in proliferation pathways were more frequent in responders. In conclusion, our findings indicate that p53, NOTCH1 and exon 20 EGFR mutations seem to be related to TKI resistance. KRAS mutations do not appear to influence the TKI response, although G12C mutation is more frequent in non-responders. Finally, the use of highly sensitive methodologies could lead to the identification of under-represented EGFR mutations potentially associated with TKI sensitivity.

Original languageEnglish
Pages (from-to)747-757
Number of pages11
JournalInternational Journal of Molecular Sciences
Volume16
Issue number1
DOIs
Publication statusPublished - Dec 31 2015

Keywords

  • EGFR wt
  • Endoplasmic reticulum stress
  • KRAS
  • NSCLC
  • p53

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Spectroscopy
  • Inorganic Chemistry
  • Catalysis
  • Molecular Biology
  • Computer Science Applications

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  • Cite this

    Ulivi, P., Delmonte, A., Chiadini, E., Calistri, D., Papi, M., Mariotti, M., Verlicchi, A., Ragazzini, A., Capelli, L., Gamboni, A., Puccetti, M., Dubini, A., Burgio, M. A., Casanova, C., Crinò, L., Amadori, D., & Dazzi, C. (2015). Gene mutation analysis in EGFR wild type NSCLC responsive to erlotinib: Are there features to guide patient selection? International Journal of Molecular Sciences, 16(1), 747-757. https://doi.org/10.3390/ijms16010747