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Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing

We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then e...

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Autores principales: Zhang, Chenlu, Wang, Zhiming, Zhuang, Rongyuan, Guo, Xi, Feng, Yi, Shen, Feng, Liu, Wenshuai, Zhang, Yong, Tong, Hanxing, Sun, Wending, Liu, Jun, Wang, Guan, Dai, Chun, Lu, Weiqi, Zhou, Yuhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568619/
https://www.ncbi.nlm.nih.gov/pubmed/33116613
http://dx.doi.org/10.2147/OTT.S270481
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author Zhang, Chenlu
Wang, Zhiming
Zhuang, Rongyuan
Guo, Xi
Feng, Yi
Shen, Feng
Liu, Wenshuai
Zhang, Yong
Tong, Hanxing
Sun, Wending
Liu, Jun
Wang, Guan
Dai, Chun
Lu, Weiqi
Zhou, Yuhong
author_facet Zhang, Chenlu
Wang, Zhiming
Zhuang, Rongyuan
Guo, Xi
Feng, Yi
Shen, Feng
Liu, Wenshuai
Zhang, Yong
Tong, Hanxing
Sun, Wending
Liu, Jun
Wang, Guan
Dai, Chun
Lu, Weiqi
Zhou, Yuhong
author_sort Zhang, Chenlu
collection PubMed
description We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then experienced recurrence or progression of the disease. During the treatment, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were applied to monitor potential drug-induced gene mutation and expression changes. A novel, secondary mutation in ALK exon 23 (L1196Q) was identified in patient 1 after alectinib resistance developed. Guided by this result, a newer ALK inhibitor, ceritinib was prescribed. The patient was able to achieve a partial response (PR) and is in good condition as of the manuscript date. On the contrary, there was no secondary mutation identified in ALK in patient 2 after drug resistance. While the expression of PTCH1, a negative regulator of the sonic hedgehog (SHH) signaling pathway, was significantly reduced at the time after the treatment with crizotinib before that of alectinib. The expression of PTCH1 was also reduced after the treatment with alectinib. It was reported that ALK can exert its biological functions partially by activating SHH signaling pathway. The down-regulation of PTCH1 suggests the compensatory activation of SHH pathway may cause resistance to ALK inhibitors in IMT. Going forward, monitoring gene mutation and expression changes through DNA and RNA sequencing will be able to offer opportunities to investigate potential mechanisms of drug resistance and will help to achieve precise prescription for better treatment outcomes.
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spelling pubmed-75686192020-10-27 Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing Zhang, Chenlu Wang, Zhiming Zhuang, Rongyuan Guo, Xi Feng, Yi Shen, Feng Liu, Wenshuai Zhang, Yong Tong, Hanxing Sun, Wending Liu, Jun Wang, Guan Dai, Chun Lu, Weiqi Zhou, Yuhong Onco Targets Ther Case Series We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then experienced recurrence or progression of the disease. During the treatment, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were applied to monitor potential drug-induced gene mutation and expression changes. A novel, secondary mutation in ALK exon 23 (L1196Q) was identified in patient 1 after alectinib resistance developed. Guided by this result, a newer ALK inhibitor, ceritinib was prescribed. The patient was able to achieve a partial response (PR) and is in good condition as of the manuscript date. On the contrary, there was no secondary mutation identified in ALK in patient 2 after drug resistance. While the expression of PTCH1, a negative regulator of the sonic hedgehog (SHH) signaling pathway, was significantly reduced at the time after the treatment with crizotinib before that of alectinib. The expression of PTCH1 was also reduced after the treatment with alectinib. It was reported that ALK can exert its biological functions partially by activating SHH signaling pathway. The down-regulation of PTCH1 suggests the compensatory activation of SHH pathway may cause resistance to ALK inhibitors in IMT. Going forward, monitoring gene mutation and expression changes through DNA and RNA sequencing will be able to offer opportunities to investigate potential mechanisms of drug resistance and will help to achieve precise prescription for better treatment outcomes. Dove 2020-10-13 /pmc/articles/PMC7568619/ /pubmed/33116613 http://dx.doi.org/10.2147/OTT.S270481 Text en © 2020 Zhang et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Case Series
Zhang, Chenlu
Wang, Zhiming
Zhuang, Rongyuan
Guo, Xi
Feng, Yi
Shen, Feng
Liu, Wenshuai
Zhang, Yong
Tong, Hanxing
Sun, Wending
Liu, Jun
Wang, Guan
Dai, Chun
Lu, Weiqi
Zhou, Yuhong
Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing
title Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing
title_full Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing
title_fullStr Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing
title_full_unstemmed Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing
title_short Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing
title_sort efficacy and resistance of alk inhibitors in two inflammatory myofibroblastic tumor patients with alk fusions assessed by whole exome and rna sequencing
topic Case Series
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568619/
https://www.ncbi.nlm.nih.gov/pubmed/33116613
http://dx.doi.org/10.2147/OTT.S270481
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