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

Amit Dipak Amin, Lingxiao Li, Soumya S. Rajan, Vijay Gokhale, Matthew J. Groysman, Praechompoo Pongtornpipat, Edgar O. Tapia, Mengdie Wang, Jonathan H Schatz

Research output: Contribution to journalArticle

9 Scopus citations

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 thatarose 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 engineeredto 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 by passing mutations when detected in resistant patient samples and highlight differences betweenthe effects of particular mutations on the two ALK fusions.

Original languageEnglish (US)
Pages (from-to)23715-23729
Number of pages15
JournalOncotarget
Volume7
Issue number17
DOIs
StatePublished - Apr 26 2016

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Keywords

  • Alectinib
  • Anaplastic lymphoma kinase
  • Ceritinib
  • Crizotinib
  • Drug resistance

ASJC Scopus subject areas

  • Oncology

Cite this

Amin, A. D., Li, L., Rajan, S. S., Gokhale, V., Groysman, M. J., Pongtornpipat, P., Tapia, E. O., Wang, M., & Schatz, J. H. (2016). Tki sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant alk+ tumors. Oncotarget, 7(17), 23715-23729. https://doi.org/10.18632/oncotarget.8173