Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783596559529672704 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7568619 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Dove |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT zhangchenlu efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT wangzhiming efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT zhuangrongyuan efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT guoxi efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT fengyi efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT shenfeng efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT liuwenshuai efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT zhangyong efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT tonghanxing efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT sunwending efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT liujun efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT wangguan efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT daichun efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT luweiqi efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing AT zhouyuhong efficacyandresistanceofalkinhibitorsintwoinflammatorymyofibroblastictumorpatientswithalkfusionsassessedbywholeexomeandrnasequencing |