Abstract 3893: Novel synergistic targets for combination therapy in Philadelphia chromosome-like acute lymphoblastic leukemia
| Autor: | Chia-hui Chen, Joseph P. Loftus, Hannah Kim, Kai Tan, Sarah K. Tasian, Kellyn Madden, Yang Y. Ding |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Cancer Research. 80:3893-3893 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2020-3893 |
| Popis: | Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like ALL) is a common leukemia subtype associated with high relapse rates and poor overall survival. Ph-like ALL has a kinase-activated gene expression signature similar to that of BCR-ABL1-rearranged ALL, but is driven by alternative mutations in JAK or ABL kinase signaling pathway genes. Preclinical studies using tyrosine kinase inhibitor (TKI) monotherapy in Ph-like ALL models demonstrate incomplete efficacy, emphasizing the need for combination therapy to improve cure rates. In these studies, we use a novel patient ‘omics data-driven approach to nominate pathways for optimal synergistic targeting in Ph-like ALL. We utilized our OptiCon algorithm (Hu et al. Nat. Comm. 2019) to analyze publicly-available genomic and transcriptomic data from patient leukemia samples. We identified synergistic gene pairs that control a maximal number of deregulated genes (for optimal efficacy) and a minimal number of unperturbed genes (to minimize toxicity) in Ph-like ALL, including a top-ranked synergistic control pair STAT5B and BAG1. STAT5B is hyperactive in different subclasses of Ph-like ALL and BAG1 (BCL2-associated athanogene1) enhances the anti-apoptotic effect of BCL-2 likely via degradation prevention. We then validated the anti-leukemic efficacy of co-targeting this pairing in Ph-like ALL cell lines and patient-derived xenograft (PDX) models. We assessed the in vitro and in vivo effects of combining the BCL-2 inhibitor venetoclax with the JAKi ruxolitinib or ABL1i dasatinib in 3 Ph-like ALL cell lines (CRLF2-rearranged/JAK-mutant MUTZ5 and MHH-cALL-4, immortalized ABL1-rearranged TVA-1) and 3 Ph-like ALL PDX models (CRLF2-rearranged/JAK-mutant ALL4364 and UP_ALL4988, ABL1-rearranged TVA-1). Co-treatment of the 3 cell lines with venetoclax and ruxolitinib or dasatinib showed synergy at all dose combinations tested, versus monotherapy (CI Citation Format: Yang Y. Ding, Kellyn Madden, Joseph P. Loftus, Hannah Kim, Chia-hui Chen, Sarah K. Tasian, Kai Tan. Novel synergistic targets for combination therapy in Philadelphia chromosome-like acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3893. |
| Databáze: | OpenAIRE |
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