Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma

Abstract Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We ge...

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Autores principales:	Seok-Young Kim, Ji Yeon Lee, Dong Hwi Kim, Hyeong -Seok Joo, Mi Ran Yun, Dongmin Jung, Jiyeon Yun, Seong Gu Heo, Beung -Chul Ahn, Chae Won Park, Kyoung Ho Pyo, You Jin Chun, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a381d185621a4cc6965c977aa42e9fc1
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spelling	oai:doaj.org-article:a381d185621a4cc6965c977aa42e9fc12021-12-02T13:34:54ZPatient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma10.1038/s41598-019-56356-42045-2322https://doaj.org/article/a381d185621a4cc6965c977aa42e9fc12019-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-56356-4https://doaj.org/toc/2045-2322Abstract Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.Seok-Young KimJi Yeon LeeDong Hwi KimHyeong -Seok JooMi Ran YunDongmin JungJiyeon YunSeong Gu HeoBeung -Chul AhnChae Won ParkKyoung Ho PyoYou Jin ChunMin Hee HongHye Ryun KimByoung Chul ChoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-12 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Seok-Young Kim Ji Yeon Lee Dong Hwi Kim Hyeong -Seok Joo Mi Ran Yun Dongmin Jung Jiyeon Yun Seong Gu Heo Beung -Chul Ahn Chae Won Park Kyoung Ho Pyo You Jin Chun Min Hee Hong Hye Ryun Kim Byoung Chul Cho Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma
description	Abstract Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.
format	article
author	Seok-Young Kim Ji Yeon Lee Dong Hwi Kim Hyeong -Seok Joo Mi Ran Yun Dongmin Jung Jiyeon Yun Seong Gu Heo Beung -Chul Ahn Chae Won Park Kyoung Ho Pyo You Jin Chun Min Hee Hong Hye Ryun Kim Byoung Chul Cho
author_facet	Seok-Young Kim Ji Yeon Lee Dong Hwi Kim Hyeong -Seok Joo Mi Ran Yun Dongmin Jung Jiyeon Yun Seong Gu Heo Beung -Chul Ahn Chae Won Park Kyoung Ho Pyo You Jin Chun Min Hee Hong Hye Ryun Kim Byoung Chul Cho
author_sort	Seok-Young Kim
title	Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma
title_short	Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma
title_full	Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma
title_fullStr	Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma
title_full_unstemmed	Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma
title_sort	patient-derived cells to guide targeted therapy for advanced lung adenocarcinoma
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/a381d185621a4cc6965c977aa42e9fc1
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Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma

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