Preclinical evaluation of the Hsp90 inhibitor SNX-5422 in ibrutinib resistant CLL
Open Access
- 24 February 2021
- journal article
- letter
- Published by Springer Science and Business Media LLC in Journal of Hematology & Oncology
- Vol. 14 (1), 1-5
- https://doi.org/10.1186/s13045-021-01039-9
Abstract
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.Keywords
Funding Information
- National Cancer Institute (R35 CA197734-01, P01 CA81534, K12 CA133250, P30 CA016058)
- Sullivan Foundation
- Leukemia and Lymphoma Society (3077-12)
- D. Warren Brown Family Foundation
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