Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma

Giuseppina Improta, Angela Zupa, Maria Iole Natalicchio, Lorenza Sisinni, Anna Marinaccio, Giovanni Bozza, Giulia Vita, Michele Aieta, Matteo Landriscina

Research output: Contribution to journalArticle

Abstract

Exons 19-21 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy.

Original languageEnglish
Pages (from-to)28
JournalMedical Oncology
Volume35
Issue number3
DOIs
Publication statusPublished - Jan 31 2018

Fingerprint

Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Exons
Mutation
Frameshift Mutation
Computer Simulation
Sequence Deletion
Therapeutics
Nucleotides
Biomarkers

Keywords

  • Journal Article

Cite this

Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma. / Improta, Giuseppina; Zupa, Angela; Natalicchio, Maria Iole; Sisinni, Lorenza; Marinaccio, Anna; Bozza, Giovanni; Vita, Giulia; Aieta, Michele; Landriscina, Matteo.

In: Medical Oncology, Vol. 35, No. 3, 31.01.2018, p. 28.

Research output: Contribution to journalArticle

Improta, Giuseppina ; Zupa, Angela ; Natalicchio, Maria Iole ; Sisinni, Lorenza ; Marinaccio, Anna ; Bozza, Giovanni ; Vita, Giulia ; Aieta, Michele ; Landriscina, Matteo. / Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma. In: Medical Oncology. 2018 ; Vol. 35, No. 3. pp. 28.
@article{74c62495fae24ea28e01fd3d45ec796e,
title = "Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma",
abstract = "Exons 19-21 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy.",
keywords = "Journal Article",
author = "Giuseppina Improta and Angela Zupa and Natalicchio, {Maria Iole} and Lorenza Sisinni and Anna Marinaccio and Giovanni Bozza and Giulia Vita and Michele Aieta and Matteo Landriscina",
year = "2018",
month = "1",
day = "31",
doi = "10.1007/s12032-018-1078-7",
language = "English",
volume = "35",
pages = "28",
journal = "Medical Oncology",
issn = "1357-0560",
publisher = "Humana Press Inc.",
number = "3",

}

TY - JOUR

T1 - Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma

AU - Improta, Giuseppina

AU - Zupa, Angela

AU - Natalicchio, Maria Iole

AU - Sisinni, Lorenza

AU - Marinaccio, Anna

AU - Bozza, Giovanni

AU - Vita, Giulia

AU - Aieta, Michele

AU - Landriscina, Matteo

PY - 2018/1/31

Y1 - 2018/1/31

N2 - Exons 19-21 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy.

AB - Exons 19-21 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy.

KW - Journal Article

U2 - 10.1007/s12032-018-1078-7

DO - 10.1007/s12032-018-1078-7

M3 - Article

VL - 35

SP - 28

JO - Medical Oncology

JF - Medical Oncology

SN - 1357-0560

IS - 3

ER -