GSK3 inhibitor enhances gemtuzumab ozogamicin-induced apoptosis in primary human leukemia cells by overcoming multiple mechanisms of resistance

patients who suffer from severe toxicity at standard GO doses. It is also

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currently used in combination with daunorubicin and cytarabine, but

replacing these with a less toxic GSK3 inhibitor may produce similar or

stronger effects while reducing side effects.

In addition, resistance, which is a major problem in GO treatment,

may be overcome by using it in combination with a GSK3 inhibitor.

Among attempts to overcome ADC resistance, improvements in ADC

linkers and payloads have been the most commonly used, and have

shown the greatest success [18, 48]. Further, attempts are being made

to overcome the ADC resistance mechanism itself with other drugs. For

example, MDR-1 inhibitors can be expected to increase the intracellular concentration of payload [49]. Also, HSP90 inhibitors are known to

block endosomal recycling and are expected to increase trafficking of

Her2 and antibody complexes [50]. Accordingly, combinations of several ADCs with MDR-1 inhibitors or HSP90 inhibitors are expected

to show clinical efficacy. Of concern, however, some agents, such as

MDR-1 inhibitors and Bcl-2 inhibitors, can counter only one mode of

resistance, limiting their effectiveness. However, as our present findings show, combination with GSK3 inhibitors would increase the range

of patients who could benefit. Combination therapy may also be effective with other ADCs having lysosomally degradable linkers and similar

mechanisms of resistance against the drug payload.

AUTHOR CONTRIBUTIONS

AI designed and performed experiments, analyzed and interpreted the

data, and wrote the manuscript. YM, SK, HG, KK, SK, KY, HM, and HM

provided critical feedback and support. YM, SK, YM, YM, SO, HM, AK,

RS, KK, AH, SN, HG, KK, SK, and KY collected patient samples and data.

HM supervised the project. All authors reviewed the manuscript and

approved its final version.

ACKNOWLEDGMENTS

The authors sincerely thank the patients for their participation. They

also thank Dr. Yosuke Minami and Dr. Hideki Nakakuma for their valuable contribution and the many colleagues who read early drafts of

the manuscript and provided critical comments and suggestions. This

study was supported by research funding from Takeda Pharmaceutical

Company, Daiichi-Sankyo, Sysmex Corporation.

CONFLICT OF INTEREST

HM has a COI with Pfizer (honoraria). All other authors declare no

conflict of interest with the work presented in this study.

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INASE ET AL .

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INASE ET AL .

How to cite this article: Inase A, Maimaitili Y, Kimbara S,

Mizutani Y, Miyata Y, Ohata S, et al. GSK3 inhibitor enhances

gemtuzumab ozogamicin-induced apoptosis in primary human

leukemia cells by overcoming multiple mechanisms of

SUPPORTING INFORMATION

resistance. eJHaem. 2023;4:153–164.

Additional supporting information can be found online in the Support-

https://doi.org/10.1002/jha2.600

ing Information section at the end of this article.

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