Oncotarget

Research Papers:

ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells

Benigno C. Valdez _, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto and Borje S. Andersson

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Oncotarget. 2024; 15:220-231. https://doi.org/10.18632/oncotarget.28563

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Abstract

Benigno C. Valdez1, Bin Yuan1, David Murray2, Jeremy L. Ramdial1, Uday Popat1, Yago Nieto1 and Borje S. Andersson1

1 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2 Department of Oncology, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada

Correspondence to:

Benigno C. Valdez, email: [email protected]

Keywords: acute myeloid leukemia; pre-transplant regimens; venetoclax; thiotepa; busulfan

Received: December 04, 2023     Accepted: February 12, 2024     Published: March 14, 2024

Copyright: © 2024 Valdez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.


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