Oncotarget

Research Papers:

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 and Jonathan H. Schatz _

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Oncotarget. 2016; 7:23715-23729. https://doi.org/10.18632/oncotarget.8173

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Abstract

Amit Dipak Amin1,*, Lingxiao Li1,*, Soumya S. Rajan2, Vijay Gokhale3,4, Matthew J. Groysman5, Praechompoo Pongtornpipat3, Edgar O. Tapia6, Mengdie Wang6, Jonathan H. Schatz1

1Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

2Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA

3BIO5 Institute, University of Arizona, Tucson, AZ, USA

4Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA

5Undergraduate Biology Research Program, University of Arizona, Tucson, AZ, USA

6Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA

*These authors contributed equally to this work

Correspondence to:

Jonathan H. Schatz, e-mail: jschatz@miami.edu

Keywords: anaplastic lymphoma kinase, drug resistance, crizotinib, ceritinib, alectinib

Received: May 22, 2015     Accepted: March 02, 2016     Published: March 18, 2016

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.


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