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Published on: January 7, 2019
Lasalocid A selectively induces the degradation of MYD88 in lymphomas harboring the MYD88 L265P mutation
Wei Li1,2, Ruirui Wang1, Junhao Wang2
1Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Abstract:
Myeloid differentiation primary response protein 88 (MYD88) is a key adaptor molecule in the signaling pathways of toll-like receptor and interleukin-1 receptor. A somatic mutation resulting in a leucine-to-proline change at position 265 of the MYD88 protein (MYD88 L265P) is one of the most prevalent oncogenic mutations found in patients with hematological malignancies. In this study, we used high-throughput screening to identify lasalocid A as a potent small molecule that selectively inhibited the viability of lymphoma cells expressing MYD88 L265P and the associated activation of NF-κB. Further investigations using CRISPR-CRISPR-associated protein 9 genetic screening, proteomics, and biochemical assays revealed that lasalocid A directly binds to the MYD88 L265P protein, enhancing its interaction with the ubiquitin ligase RNF5. This interaction promotes MYD88 degradation through the ubiquitin-dependent proteasomal pathway, specifically in lymphomas with the MYD88 L265P mutation. Lasalocid A exhibited strong antitumor efficacy in xenograft mouse models, induced disease remission in ibrutinib-resistant lymphomas, and showed synergistic activity with the B-cell lymphoma 2 inhibitor venetoclax. This study highlights the potential of inducing MYD88 L265P degradation using small molecules, offering promising strategies for treating lymphomas that harbor the MYD88 L265P mutation.
Insights
Lasalocid A targets the MYD88 L265P mutation in lymphoma by promoting protein degradation. This approach shows promise for treating hematological malignancies, including ibrutinib-resistant cases.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Myeloid differentiation primary response protein 88 (MYD88) is crucial in toll-like receptor and interleukin-1 receptor signaling.
- The MYD88 L265P mutation is a common oncogenic driver in hematological malignancies.
- Targeting MYD88 L265P represents a potential therapeutic strategy for lymphomas.
Purpose of the Study:
- To identify small molecules that selectively inhibit lymphoma cells with the MYD88 L265P mutation.
- To elucidate the mechanism of action of identified inhibitors.
- To evaluate the therapeutic potential of these inhibitors in preclinical models.
Main Methods:
- High-throughput screening to identify small molecule inhibitors.
- CRISPR-CRISPR-associated protein 9 genetic screening.
- Proteomics and biochemical assays to determine drug-target interactions.
- In vivo studies using xenograft mouse models.
Main Results:
- Lasalocid A was identified as a potent inhibitor of MYD88 L265P-mutated lymphoma cells.
- Lasalocid A directly binds MYD88 L265P, enhancing its degradation via the ubiquitin-proteasomal pathway.
- Lasalocid A demonstrated significant antitumor efficacy in vivo, including in ibrutinib-resistant models.
- Synergistic activity was observed with venetoclax, a B-cell lymphoma 2 inhibitor.
Conclusions:
- Targeting MYD88 L265P degradation with small molecules is a viable therapeutic strategy.
- Lasalocid A shows significant potential for treating MYD88 L265P-driven lymphomas.
- Combination therapies involving lasalocid A may overcome resistance and improve treatment outcomes.
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