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Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma

PURPOSE: Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targete...

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Autores principales: Kim, Seok-Young, Kim, Sang-Min, Lim, Sumin, Lee, Ji Yeon, Choi, Su-Jin, Yang, San-Duk, Yun, Mi Ran, Kim, Chang Gon, Gu, Seo Rin, Park, Chaewon, Park, A-Young, Lim, Sun Min, Heo, Seong Gu, Kim, HyunKi, Cho, Byoung Chul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401503/
https://www.ncbi.nlm.nih.gov/pubmed/34083237
http://dx.doi.org/10.1158/1078-0432.CCR-20-5026
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author Kim, Seok-Young
Kim, Sang-Min
Lim, Sumin
Lee, Ji Yeon
Choi, Su-Jin
Yang, San-Duk
Yun, Mi Ran
Kim, Chang Gon
Gu, Seo Rin
Park, Chaewon
Park, A-Young
Lim, Sun Min
Heo, Seong Gu
Kim, HyunKi
Cho, Byoung Chul
author_facet Kim, Seok-Young
Kim, Sang-Min
Lim, Sumin
Lee, Ji Yeon
Choi, Su-Jin
Yang, San-Duk
Yun, Mi Ran
Kim, Chang Gon
Gu, Seo Rin
Park, Chaewon
Park, A-Young
Lim, Sun Min
Heo, Seong Gu
Kim, HyunKi
Cho, Byoung Chul
author_sort Kim, Seok-Young
collection PubMed
description PURPOSE: Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets. EXPERIMENTAL DESIGN: Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts. RESULTS: PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions. CONCLUSIONS: We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
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spelling pubmed-94015032023-01-05 Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma Kim, Seok-Young Kim, Sang-Min Lim, Sumin Lee, Ji Yeon Choi, Su-Jin Yang, San-Duk Yun, Mi Ran Kim, Chang Gon Gu, Seo Rin Park, Chaewon Park, A-Young Lim, Sun Min Heo, Seong Gu Kim, HyunKi Cho, Byoung Chul Clin Cancer Res Translational Cancer Mechanisms and Therapy PURPOSE: Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets. EXPERIMENTAL DESIGN: Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts. RESULTS: PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions. CONCLUSIONS: We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies. American Association for Cancer Research 2021-08-01 2021-06-03 /pmc/articles/PMC9401503/ /pubmed/34083237 http://dx.doi.org/10.1158/1078-0432.CCR-20-5026 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Translational Cancer Mechanisms and Therapy
Kim, Seok-Young
Kim, Sang-Min
Lim, Sumin
Lee, Ji Yeon
Choi, Su-Jin
Yang, San-Duk
Yun, Mi Ran
Kim, Chang Gon
Gu, Seo Rin
Park, Chaewon
Park, A-Young
Lim, Sun Min
Heo, Seong Gu
Kim, HyunKi
Cho, Byoung Chul
Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
title Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
title_full Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
title_fullStr Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
title_full_unstemmed Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
title_short Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
title_sort modeling clinical responses to targeted therapies by patient-derived organoids of advanced lung adenocarcinoma
topic Translational Cancer Mechanisms and Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401503/
https://www.ncbi.nlm.nih.gov/pubmed/34083237
http://dx.doi.org/10.1158/1078-0432.CCR-20-5026
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