| Literature DB >> 30282833 |
Elisa Ten Hacken1, Rebecca Valentin1, Fara Faye D Regis1, Jing Sun1, Shanye Yin2, Lillian Werner3, Jing Deng1, Michaela Gruber1, Jessica Wong1, Mei Zheng4, Amy L Gill1, Michael Seiler5, Peter Smith5, Michael Thomas5, Silvia Buonamici5, Emanuela M Ghia6, Ekaterina Kim7, Laura Z Rassenti6, Jan A Burger7, Thomas J Kipps6, Matthew L Meyerson1,8,9, Pavan Bachireddy1,8,10, Lili Wang1,8, Robin Reed2, Donna Neuberg3, Ruben D Carrasco4,11, Angela N Brooks12, Anthony Letai1,8,10, Matthew S Davids1,8,10, Catherine J Wu1,8,9,10.
Abstract
The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.Entities:
Keywords: Apoptosis inhibitors; Cancer; Hematology; Therapeutics; Transcription
Year: 2018 PMID： 30282833 PMCID： PMC6237462 DOI： 10.1172/jci.insight.121438
Source DB: PubMed Journal: JCI Insight ISSN： 2379-3708