TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors

Persistent Link:
http://hdl.handle.net/10150/617186
Title:
TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors
Author:
Amin, Amit Dipak; Li, Lingxiao; Rajan, Soumya S.; Gokhale, Vijay; Groysman, Matthew J.; Pongtornpipat, Praechompoo; Tapia, Edgar O.; Wang, Mengdie; Schatz, Jonathan H.
Affiliation:
Univ Arizona, Inst BIO5; Univ Arizona, Dept Pharmacol & Toxicol; Univ Arizona, Undergrad Biol Res Program; Univ Arizona, Canc Biol Grad Interdisciplinary Program
Issue Date:
2016-04-25
Publisher:
IMPACT JOURNALS LLC
Citation:
TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors 2016 Oncotarget
Journal:
Oncotarget
Rights:
Creative Commons Attribution License (CCAL)
Collection Information:
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
Abstract:
The anaplastic lymphoma kinase (ALK) protein drives tumorigenesis in subsets of several tumors through chromosomal rearrangements that express and activate its C-terminal kinase domain. In addition, germline predisposition alleles and acquired mutations are found in the full-length protein in the pediatric tumor neuroblastoma. ALK-specific tyrosine kinase inhibitors (TKIs) have become important new drugs for ALK-driven lung cancer, but acquired resistance via multiple mechanisms including kinase-domain mutations eventually develops, limiting median progression-free survival to less than a year. Here we assess the impact of several kinase-domain mutations that arose during TKI resistance selections of ALK+ anaplastic large-cell lymphoma (ALCL) cell lines. These include novel variants with respect to ALK-fusion cancers, R1192P and T1151M, and with respect to ALCL, F1174L and I1171S. We assess the effects of these mutations on the activity of six clinical inhibitors in independent systems engineered to depend on either the ALCL fusion kinase NPM-ALK or the lung-cancer fusion kinase EML4-ALK. Our results inform treatment strategies with a likelihood of bypassing mutations when detected in resistant patient samples and highlight differences between the effects of particular mutations on the two ALK fusions.
ISSN:
1949-2553
DOI:
10.18632/oncotarget.8173
Keywords:
anaplastic lymphoma kinase; drug resistance; crizotinib; ceritinib; alectinib
Version:
Final published version
Sponsors:
NIH/NCGI [1R01CA190696-01]
Additional Links:
http://www.oncotarget.com/abstract/8173

Full metadata record

DC FieldValue Language
dc.contributor.authorAmin, Amit Dipaken
dc.contributor.authorLi, Lingxiaoen
dc.contributor.authorRajan, Soumya S.en
dc.contributor.authorGokhale, Vijayen
dc.contributor.authorGroysman, Matthew J.en
dc.contributor.authorPongtornpipat, Praechompooen
dc.contributor.authorTapia, Edgar O.en
dc.contributor.authorWang, Mengdieen
dc.contributor.authorSchatz, Jonathan H.en
dc.date.accessioned2016-07-19T02:19:51Z-
dc.date.available2016-07-19T02:19:51Z-
dc.date.issued2016-04-25-
dc.identifier.citationTKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors 2016 Oncotargeten
dc.identifier.issn1949-2553-
dc.identifier.doi10.18632/oncotarget.8173-
dc.identifier.urihttp://hdl.handle.net/10150/617186-
dc.description.abstractThe anaplastic lymphoma kinase (ALK) protein drives tumorigenesis in subsets of several tumors through chromosomal rearrangements that express and activate its C-terminal kinase domain. In addition, germline predisposition alleles and acquired mutations are found in the full-length protein in the pediatric tumor neuroblastoma. ALK-specific tyrosine kinase inhibitors (TKIs) have become important new drugs for ALK-driven lung cancer, but acquired resistance via multiple mechanisms including kinase-domain mutations eventually develops, limiting median progression-free survival to less than a year. Here we assess the impact of several kinase-domain mutations that arose during TKI resistance selections of ALK+ anaplastic large-cell lymphoma (ALCL) cell lines. These include novel variants with respect to ALK-fusion cancers, R1192P and T1151M, and with respect to ALCL, F1174L and I1171S. We assess the effects of these mutations on the activity of six clinical inhibitors in independent systems engineered to depend on either the ALCL fusion kinase NPM-ALK or the lung-cancer fusion kinase EML4-ALK. Our results inform treatment strategies with a likelihood of bypassing mutations when detected in resistant patient samples and highlight differences between the effects of particular mutations on the two ALK fusions.en
dc.description.sponsorshipNIH/NCGI [1R01CA190696-01]en
dc.language.isoenen
dc.publisherIMPACT JOURNALS LLCen
dc.relation.urlhttp://www.oncotarget.com/abstract/8173en
dc.rightsCreative Commons Attribution License (CCAL)en
dc.subjectanaplastic lymphoma kinaseen
dc.subjectdrug resistanceen
dc.subjectcrizotiniben
dc.subjectceritiniben
dc.subjectalectiniben
dc.titleTKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumorsen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Inst BIO5en
dc.contributor.departmentUniv Arizona, Dept Pharmacol & Toxicolen
dc.contributor.departmentUniv Arizona, Undergrad Biol Res Programen
dc.contributor.departmentUniv Arizona, Canc Biol Grad Interdisciplinary Programen
dc.identifier.journalOncotargeten
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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