Elucidation of Acquired Resistance to Bcl-2 and MDM2 Inhibitors in Acute Leukemia In Vitro and In Vivo
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Abstract
Purpose: Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263, and the MDM2 inhibitor SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance. Elucidation of acquired resistance mechanisms and development of strategies to overcome the resistance are critical for their successful clinical development. Experimental Design: We employed RS4;11 and MV4;11 cell lines, two acute leukemia models, to investigate acquired resistance mechanisms for both drugs in vitro and in vivo and evaluated several treatment regimens in xenograft mouse models to improve long-term, complete tumor regression. Results: Resistance to either SAR405838 or ABT-263 (or its analogue ABT-737) develops in acute leukemia models in vitro and in vivo. RS4;11 and MV4;11 tumors treated with SAR405838 acquire resistance to the drug by mutation of the TP53 gene or compromise of p53 protein function. RS4;11 tumors treated with either ABT-263 or ABT-737 acquire resistance primarily through downregulation of BAX but not BAK. When acute leukemia cells become highly resistant to the MDM2 inhibitor, they retain their sensitivity to the Bcl-2 inhibitors, or vice versa. Certain sequential or combination treatment of SAR405838 and ABT-263 can achieve longer-term tumor regression than treatment with either agent alone. Conclusions: Our study provides new insights into the mechanisms of acquired resistance of Bcl-2 and MDM2 inhibitors in acute leukemia models and suggests that certain sequential or combination treatment of these two distinct classes of apoptosis-inducing agents should be tested as new treatment strategies for acute leukemia in the clinic. Clin Cancer Res; 21(11); 2558–68. ©2015 AACR.
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SAR-405838 is a spiroxindole-based MDM2 inhibitor that demonstrates strong binding affinity to MDM2 and effective growth inhibition activity.
“SAR-405838 (143) is a spiroxindole-based MDM2 inhibitor that demonstrates strong binding affinity to MDM2 and effective growth inhibition activity.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [382]
SAR-405838 has shown high selectivity for cancer cell lines with mutations or deletions of p53.
“It has shown high selectivity for cancer cell lines with mutations or deletions of p53.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [382]
In the SJSA-1 model, SAR-405838 effectively inhibited the growth of tumor cell lines and induced apoptosis in ABTR1 and ABTR2 sublines in a dose-dependent manner.
“In the SJSA-1 model, SAR-405838 effectively inhibited the growth of tumor cell lines and induced apoptosis in ABTR1 and ABTR2 sublines in a dose-dependent manner.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [382]
In mouse xenograft models of SJSA1, RS411, LNCaP, and HCT-116, SAR-405838 achieved lasting tumor regression or complete inhibition of tumor growth under a well-tolerated dose regimen.
“In mouse xenograft models of SJSA1, RS411, LNCaP, and HCT-116, SAR-405838 achieved lasting tumor regression or complete inhibition of tumor growth under a well-tolerated dose regimen.381,382”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [382]
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- Authors
- Hoffman-Luca, C. G., Ziazadeh, D., McEachern, D., Zhao, Y., Sun, W., Debussche, L., & Wang, S.
- Affiliations
- University of Michigan (US)
- 4Sanofi Oncology, Vitry-sur-Seine, France.
- Corresponding author
- Wang, Shaomeng
- Venue
- Clinical Cancer Research
- Published
- 2015-05-31
- Volume
- 21
- Issue
- 11
- Pages
- 2558-2568
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4957562
- OpenAlex
- W2081953771
- Cited by
- 52
- References
- 49
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 8 · 2018: 5 · 2017: 5 · 2016: 3 · 2015: 3
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA121279)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- acquired drug resistance, BCL-2 inhibitor, MDM2 inhibitors, navitoclax, ABT-737, acute leukemia, TP53 mutation, p53 function, Bak, combination therapy, sequential therapy, xenograft mouse model, RS4, apoptosis
- MeSH terms
- Animals, Biphenyl Compounds, Humans, Indoles, Leukemia, Nitrophenols, Piperazines, Spiro Compounds, Sulfonamides, Apoptosis, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-bcl-2, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Proto-Oncogene Proteins c-mdm2
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