Cargando…

Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)

BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective s...

Descripción completa

Detalles Bibliográficos
Autores principales: Lim, Sun Min, Kim, Hye Ryun, Cho, Eun Kyung, Min, Young Joo, Ahn, Jin Seok, Ahn, Myung-Ju, Park, Keunchil, Cho, Byoung Chul, Lee, Ji-Hyun, Jeong, Hye Cheol, Kim, Eun Kyung, Kim, Joo-Hang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095002/
https://www.ncbi.nlm.nih.gov/pubmed/27121209
http://dx.doi.org/10.18632/oncotarget.8904
_version_ 1782465211420114944
author Lim, Sun Min
Kim, Hye Ryun
Cho, Eun Kyung
Min, Young Joo
Ahn, Jin Seok
Ahn, Myung-Ju
Park, Keunchil
Cho, Byoung Chul
Lee, Ji-Hyun
Jeong, Hye Cheol
Kim, Eun Kyung
Kim, Joo-Hang
author_facet Lim, Sun Min
Kim, Hye Ryun
Cho, Eun Kyung
Min, Young Joo
Ahn, Jin Seok
Ahn, Myung-Ju
Park, Keunchil
Cho, Byoung Chul
Lee, Ji-Hyun
Jeong, Hye Cheol
Kim, Eun Kyung
Kim, Joo-Hang
author_sort Lim, Sun Min
collection PubMed
description BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. METHODS: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). RESULTS: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P<0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders. CONCLUSION: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163).
format Online
Article
Text
id pubmed-5095002
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-50950022016-11-22 Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium) Lim, Sun Min Kim, Hye Ryun Cho, Eun Kyung Min, Young Joo Ahn, Jin Seok Ahn, Myung-Ju Park, Keunchil Cho, Byoung Chul Lee, Ji-Hyun Jeong, Hye Cheol Kim, Eun Kyung Kim, Joo-Hang Oncotarget Research Paper BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. METHODS: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). RESULTS: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P<0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders. CONCLUSION: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163). Impact Journals LLC 2016-04-21 /pmc/articles/PMC5095002/ /pubmed/27121209 http://dx.doi.org/10.18632/oncotarget.8904 Text en Copyright: © 2016 Lim et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Lim, Sun Min
Kim, Hye Ryun
Cho, Eun Kyung
Min, Young Joo
Ahn, Jin Seok
Ahn, Myung-Ju
Park, Keunchil
Cho, Byoung Chul
Lee, Ji-Hyun
Jeong, Hye Cheol
Kim, Eun Kyung
Kim, Joo-Hang
Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)
title Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)
title_full Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)
title_fullStr Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)
title_full_unstemmed Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)
title_short Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)
title_sort targeted sequencing identifies genetic alterations that confer primary resistance to egfr tyrosine kinase inhibitor (korean lung cancer consortium)
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095002/
https://www.ncbi.nlm.nih.gov/pubmed/27121209
http://dx.doi.org/10.18632/oncotarget.8904
work_keys_str_mv AT limsunmin targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT kimhyeryun targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT choeunkyung targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT minyoungjoo targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT ahnjinseok targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT ahnmyungju targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT parkkeunchil targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT chobyoungchul targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT leejihyun targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT jeonghyecheol targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT kimeunkyung targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium
AT kimjoohang targetedsequencingidentifiesgeneticalterationsthatconferprimaryresistancetoegfrtyrosinekinaseinhibitorkoreanlungcancerconsortium