Preclinical evaluation of the Hsp90 inhibitor SNX-5422 in ibrutinib resistant CLL

Autor: Alexander Prouty, Jennifer A. Woyach, Amy Lehman, Bonnie K. Harrington, Ronni Wasmuth, Eric Orlemans, Erin Hertlein, Timothy L. Chen, Jean Truxall, Deepa Sampath, Robert A. Baiocchi, Shelby Sloan, Lapo Alinari, John C. Byrd
Rok vydání: 2020
Předmět:
Cancer Research
medicine.medical_specialty
Indazoles
Chronic lymphocytic leukemia
Glycine
Antineoplastic Agents
Hsp90
lcsh:RC254-282
Hsp90 inhibitor
chemistry.chemical_compound
Mice
Piperidines
In vivo
immune system diseases
Internal medicine
hemic and lymphatic diseases
Cell Line
Tumor
medicine
Bruton's tyrosine kinase
Animals
Humans
HSP90 Heat-Shock Proteins
Molecular Biology
Protein Kinase Inhibitors
Letter to the Editor
Hematology
biology
lcsh:RC633-647.5
business.industry
Adenine
breakpoint cluster region
lcsh:Diseases of the blood and blood-forming organs
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
Oncology
chemistry
Drug Resistance
Neoplasm
BTK
Ibrutinib
Benzamides
Cancer research
biology.protein
business
Progressive disease
Zdroj: Journal of Hematology & Oncology
Journal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-5 (2021)
ISSN: 1756-8722
Popis: B-cell receptor (BCR) antagonists such as the BTK inhibitor ibrutinib have proven to effectively target chronic lymphocytic leukemia (CLL) tumor cells, leading to impressive response rates in these patients. However patients do still relapse on ibrutinib, and the progressive disease is often quite aggressive requiring immediate treatment. Several strategies are being pursued to treat patients who relapse on ibrutinib therapy. As the most common form of relapse is the development of a mutant form of BTK which limits ibrutinib binding, agents which lead to degradation of the BTK protein are a promising strategy. Our study explores the efficacy of the Hsp90 inhibitor, SNX-5422, in CLL. The SNX Hsp90 inhibitor was effective in primary CLL cells, as well as B-cell lines expressing either BTK wild type or C481 mutant BTK, which has been identified as the primary resistance mechanism to ibrutinib in CLL patients. Furthermore the combination of SNX-5422 and ibrutinib provided a remarkable in vivo survival benefit in the Eμ-TCL1 mouse model of CLL compared to the vehicle or single agent groups (51 day median survival in the vehicle and ibrutinib groups versus 100 day median survival in the combination). We report here preclinical data suggesting that the Hsp90 inhibitor SNX-5422, which has been pursued in clinical trials in both solid tumor and hematological malignancies, is a potential therapy for ibrutinib resistant CLL. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01039-9.
Databáze: OpenAIRE
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