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AT ‐101 downregulates BCL 2 and MCL 1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and W aldenström macroglobulinaemia
Author(s) -
Paulus Aneel,
Chitta Kasyapa,
Akhtar Sharoon,
Personett David,
Miller Kena C.,
Thompson Kevin J.,
Carr Jennifer,
Kumar Shaji,
Roy Vivek,
Ansell Stephen M.,
Mikhael Joseph R.,
Dispenzieri Angela,
Reeder Craig B.,
Rivera Candido E.,
Foran James,
ChananKhan Asher
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12633
Subject(s) - lenalidomide , dexamethasone , multiple myeloma , cytotoxic t cell , pharmacology , chemistry , cancer research , medicine , immunology , biochemistry , in vitro
Summary Multiple myeloma, the second most common haematological malignancy in the U.S., is currently incurable. Disruption of the intrinsic apoptotic pathway by BCL 2 and MCL 1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL 2 or MCL 1. Thus, we investigated the anti‐tumour effects of a pan‐ BCL 2 inhibitor, AT ‐101, which has high binding specificity for BCL 2 and MCL 1 in preclinical models of plasma cell cancers ( M ultiple myeloma and W aldenström macroglobulinaemia). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL 2 family members. AT ‐101 was able to downregulate BCL 2 and MCL 1 in all plasma cell cancer models and induced apoptotic cell death in a caspase‐dependent manner by altering mitochondrial membrane permeability. This cytotoxic effect and BCL 2 downregulation were further potentiated when AT ‐101 was combined with lenalidomide/dexamethasone ( LDA ). NanoString nCounter m RNA quantification and I ngenuity P athways A nalysis revealed differential changes in the CCNA 2, FRZB , FYN , IRF 1, PTPN 11 genes in LDA ‐treated cells. In summary, we describe for the first time the cellular and molecular events associated with the use of AT ‐101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy.