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BCL-2 Family Proteins as 5-Azacytidine-sensitizing Targets and Determinants of Response in Myeloid Malignancies

BCL-2 Family Proteins as 5-Azacytidine-sensitizing Targets and Determinants of Response in Myeloid Malignancies

J M Bogenberger, S M Kornblau, W E Pierceall, R Lena, D Chow, C-X Shi, J Mantei, G Ahmann, I M Gonzales, A Choudhary, R Valdez, J Camoriano, V Fauble, R E Tiedemann, Y H Qiu, K R Coombes, M Cardone, E Braggio, etc.

Leukemia. 2014 Aug;28(8):1657-65.

PMID: 24451410

Abstract:

Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.

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TIT9316	CombiTitrant 5 XL			Price

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