TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations

Madhu M Ouseph,1 Angela Taber,2 Humera Khurshid,3 Russell Madison,4 Bassam I Aswad,1 Murray B Resnick,1 Evgeny Yakirevich,1 Siraj M Ali,4 Nimesh R Patel11Department of Pathology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI 02903, USA; 2Division of Medical Onco...

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Autores principales:	Ouseph MM, Taber A, Khurshid H, Madison R, Aswad BI, Resnick MB, Yakirevich E, Ali SM, Patel NR
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Cancer Genomics Profiling Beta-catenin Resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b29f4543d9f24599a60ac71423440ff6
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spelling	oai:doaj.org-article:b29f4543d9f24599a60ac71423440ff62021-12-02T07:41:35ZTKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations1179-2728https://doaj.org/article/b29f4543d9f24599a60ac71423440ff62019-08-01T00:00:00Zhttps://www.dovepress.com/tki-resistant-alk-rearranged-lung-adenocarcinoma-with-secondary-ctnnb1-peer-reviewed-article-LCTThttps://doaj.org/toc/1179-2728Madhu M Ouseph,1 Angela Taber,2 Humera Khurshid,3 Russell Madison,4 Bassam I Aswad,1 Murray B Resnick,1 Evgeny Yakirevich,1 Siraj M Ali,4 Nimesh R Patel11Department of Pathology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI 02903, USA; 2Division of Medical Oncology, Miriam Hospital and Alpert Medical School at Brown University, Providence, RI 02906, USA; 3Division of Medical Oncology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI 02903, USA; 4Foundation Medicine, Inc., Cambridge, MA 02141, USAAbstract: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is an important molecular subgroup of tumors that are typically sensitive to tyrosine kinase inhibitors (TKIs). Although a substantial portion of patients benefit from TKIs, this approach is complicated by intrinsic and acquired resistance. We report a patient with ALK-rearranged NSCLC who showed an initial response to targeted therapy, but developed resistance to multiple TKIs. Serial comprehensive genomic profiling (CGP) was performed at four independent points during the clinical course. We review the pathology and clonal progression of the tumor, with CGP identifying a secondary CTNNB1 p.S45V mutation after the initiation of targeted therapy, followed by tertiary ALK p.I1171N. The presence of an alteration in a second oncogenic driver gene suggests a possible mechanism for resistance, and a secondary therapeutic target. Due to the involvement of Wnt signaling in the pathogenesis of many tumors and its association with immune evasion, a variety of therapeutic strategies are being developed to target this pathway. This case exemplifies the challenges of targeted therapeutics in the face of tumor progression, as well as the increasing role of genomics in understanding tumor biology.Keywords: cancer, genomics, profiling, beta-catenin, resistance  Ouseph MMTaber AKhurshid HMadison RAswad BIResnick MBYakirevich EAli SMPatel NRDove Medical PressarticleCancerGenomicsProfilingBeta-cateninResistanceNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENLung Cancer: Targets and Therapy, Vol Volume 10, Pp 81-86 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cancer Genomics Profiling Beta-catenin Resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Cancer Genomics Profiling Beta-catenin Resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ouseph MM Taber A Khurshid H Madison R Aswad BI Resnick MB Yakirevich E Ali SM Patel NR TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations
description	Madhu M Ouseph,1 Angela Taber,2 Humera Khurshid,3 Russell Madison,4 Bassam I Aswad,1 Murray B Resnick,1 Evgeny Yakirevich,1 Siraj M Ali,4 Nimesh R Patel11Department of Pathology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI 02903, USA; 2Division of Medical Oncology, Miriam Hospital and Alpert Medical School at Brown University, Providence, RI 02906, USA; 3Division of Medical Oncology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI 02903, USA; 4Foundation Medicine, Inc., Cambridge, MA 02141, USAAbstract: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is an important molecular subgroup of tumors that are typically sensitive to tyrosine kinase inhibitors (TKIs). Although a substantial portion of patients benefit from TKIs, this approach is complicated by intrinsic and acquired resistance. We report a patient with ALK-rearranged NSCLC who showed an initial response to targeted therapy, but developed resistance to multiple TKIs. Serial comprehensive genomic profiling (CGP) was performed at four independent points during the clinical course. We review the pathology and clonal progression of the tumor, with CGP identifying a secondary CTNNB1 p.S45V mutation after the initiation of targeted therapy, followed by tertiary ALK p.I1171N. The presence of an alteration in a second oncogenic driver gene suggests a possible mechanism for resistance, and a secondary therapeutic target. Due to the involvement of Wnt signaling in the pathogenesis of many tumors and its association with immune evasion, a variety of therapeutic strategies are being developed to target this pathway. This case exemplifies the challenges of targeted therapeutics in the face of tumor progression, as well as the increasing role of genomics in understanding tumor biology.Keywords: cancer, genomics, profiling, beta-catenin, resistance
format	article
author	Ouseph MM Taber A Khurshid H Madison R Aswad BI Resnick MB Yakirevich E Ali SM Patel NR
author_facet	Ouseph MM Taber A Khurshid H Madison R Aswad BI Resnick MB Yakirevich E Ali SM Patel NR
author_sort	Ouseph MM
title	TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations
title_short	TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations
title_full	TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations
title_fullStr	TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations
title_full_unstemmed	TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations
title_sort	tki-resistant alk-rearranged lung adenocarcinoma with secondary ctnnb1 p.s45v and tertiary alk p.i1171n mutations
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/b29f4543d9f24599a60ac71423440ff6
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TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations

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