Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization

IRAK4 is a therapeutic target in myeloid malignancies, but current IRAK4 inhibitors show only modest clinical efficacy in acute myeloid leukemia, highlighting the need for combination strategies. To identify drugs with synergistic potential alongside IRAK4 inhibitors, we conducted a high-throughput screen of 2803 investigational and approved drugs in isogenic IRAK4-deficient and wild-type human AML cells. The top hit from this screen was the Cereblon E3 ligase modulator (CELMoD) CC-885. Validation in vitro and in vivo confirmed that CC-885 and related CELMoDs synergize with IRAK4 inhibitors to suppress leukemic cells. Among CC-885 substrates, GSPT1 loss showed the most pronounced effects in IRAK4-inhibited leukemic cells. Transcriptional and proteomic analyses revealed that CC-885 treatment led to c-Myc suppression in IRAK4-deficient leukemic cells. GSPT1 loss reduces translation efficiency, particularly for proteins with short half-lives, such as c-Myc. Accelerated c-Myc protein loss was confirmed following GSPT1 degradation in leukemic cells, with decreased protein stability observed following inhibition of IRAK4. These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.

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Publication Details

Journal
Leukemia
Published
2025-07-16
DOI
https://doi.org/10.1038/s41375-025-02695-3
Citations
4
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
3.22

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article

Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization

Craig J. Thomas, Mark Wunderlich, Kwangmin Choi, Kenneth D. Greis et al.
4 citations
Leukemia
Protein Degradation and Inhibitors
3.22
article

Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization

Craig J. Thomas, Mark Wunderlich, Kwangmin Choi, Kenneth D. Greis, Courtnee Clough, Carleen Maitland, Joshua Bennett, Kathleen Hueneman, Lyndsey Bolanos, Daniel T. Starczynowski, David O. Holland, Michele Ceribelli, Aishlin Hassan, Eric Vick, Ashley E. Culver‐Cochran, Tomoya Muto, Xiaohu Zhang, Crystal McKnight
article en
4 citations

Abstract

IRAK4 is a therapeutic target in myeloid malignancies, but current IRAK4 inhibitors show only modest clinical efficacy in acute myeloid leukemia, highlighting the need for combination strategies. To identify drugs with synergistic potential alongside IRAK4 inhibitors, we conducted a high-throughput screen of 2803 investigational and approved drugs in isogenic IRAK4-deficient and wild-type human AML cells. The top hit from this screen was the Cereblon E3 ligase modulator (CELMoD) CC-885. Validation in vitro and in vivo confirmed that CC-885 and related CELMoDs synergize with IRAK4 inhibitors to suppress leukemic cells. Among CC-885 substrates, GSPT1 loss showed the most pronounced effects in IRAK4-inhibited leukemic cells. Transcriptional and proteomic analyses revealed that CC-885 treatment led to c-Myc suppression in IRAK4-deficient leukemic cells. GSPT1 loss reduces translation efficiency, particularly for proteins with short half-lives, such as c-Myc. Accelerated c-Myc protein loss was confirmed following GSPT1 degradation in leukemic cells, with decreased protein stability observed following inhibition of IRAK4. These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.

LeukemiaVol. 39(9)
Cincinnati Children's Hospital Medical Center (US), National Cancer Centre Japan (JP), National Center for Advancing Translational Sciences (US), University of Cincinnati (US)
American Society of Clinical Oncology, Cincinnati Children's Hospital Medical Center, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Zero hunger
Openalex Percentile: Top 8%
Protein Degradation and Inhibitors
3.22
DOIOpen Access PDFOpenAlex
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