Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes.

Abstract

BACKGROUND:

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) shows 60-70% event free survival with standard treatments. Targeted therapies are being tested for increased benefit and/or reduced toxicity, but interactions with standard agents are not well known.

METHODS:

We exposed four ALCL cell lines to two targeted agents, crizotinib and brentuximab vedotin, and to two standard agents, doxorubicin and vinblastine. For each agent and combination, we measured apoptosis and expression of approximately 300 previously annotated genes of interest using targeted RNA-sequencing. An aurora kinase inhibitor, alisertib, was similarly tested for gene expression effects.

RESULTS:

Only crizotinib, alone or in combination, showed significant effects (adjusted P < 0.05) on expression and apoptosis. One hundred and nine of 277 gene expressions showed crizotinib-associated differential expression, mostly downregulation, 62 associated with apoptosis, and 28 associated with both crizotinib and apoptosis. Doxorubicin was antagonistic with crizotinib on gene expression and apoptosis. Brentuximab was synergistic with crizotinib in apoptosis, and not antagonistic in gene expression. Vinblastine also appeared synergistic with crizotinib but did not achieve statistical significance. Alisertib did not show significant expression changes.

CONCLUSIONS:

Our data suggest that crizotinib induces apoptosis through orderly changes in cell signaling associated with ALK inhibition. Expression effects of crizotinib and associated apoptosis are antagonized by doxorubicin, but apoptosis is synergized by brentuximab vedotin and possibly vinblastine. These findings suggest that concurrent use of crizotinib and doxorubicin may be counterproductive, while the pairing of crizotinib with brentuximab (or vinblastine) may increase efficacy. Alisertib did not induce expression changes at cytotoxic dosage.

• Authors: Sandra Hudson, Dongliang Wang, Frank Middleton, Barbara H Nevaldine, Rana Naous, Robert E Hutchison
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 65 Issue 8 Pg. e27094 (08 2018) ISSN: 1545-5017 [Electronic] United States
• PMID: 29697184 (Publication Type: Journal Article)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• Immunoconjugates
• Protein Kinase Inhibitors
• Crizotinib
• Brentuximab Vedotin
• Doxorubicin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Brentuximab Vedotin
• Cell Line, Tumor
• Crizotinib (pharmacology)
• Doxorubicin (pharmacology)
• Drug Synergism
• Gene Expression (drug effects)
• Humans
• Immunoconjugates (pharmacology)
• Lymphoma, Large-Cell, Anaplastic (pathology)
• Molecular Targeted Therapy (methods)
• Protein Kinase Inhibitors (pharmacology)