EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B cell lymphoma

The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib to block B cell receptor (BCR) signaling has achieved a remarkable clinical response in several B cell malignancies including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and impacts long-term survival of these patients. Here we demonstrate that the transcription factor EGR1 is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype (ABC) DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular ATP production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL.

 

Comments:

The passage you provided describes a study's findings related to acquired resistance to ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor used in the treatment of B cell malignancies such as mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). The study identifies a mechanism involving the transcription factor EGR1 in mediating ibrutinib resistance in these lymphomas.

Here's a summary of the key points from the passage:

1. **Ibrutinib and BCR Signaling:** Ibrutinib is effective in blocking B cell receptor (BCR) signaling and has shown clinical success in treating B cell malignancies like MCL and DLBCL.

2. **Ibrutinib Resistance and EGR1:** Acquired drug resistance to ibrutinib is a significant issue affecting long-term survival. The study found elevated expression of the transcription factor EGR1 in ibrutinib-resistant activated B-cell-like subtype (ABC) DLBCL and MCL cells. EGR1 levels increase further upon ibrutinib treatment.

3. **Role of EGR1 in Resistance:** Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. EGR1 induces metabolic reprogramming to oxidative phosphorylation (OXPHOS) by activating PDP1, a phosphatase that activates a component of the pyruvate dehydrogenase complex, leading to increased ATP production.

4. **Metabolic Reprogramming and Ibrutinib Resistance:** EGR1-mediated PDP1 activation enhances energy production, promoting the proliferation and survival of ibrutinib-resistant lymphoma cells through OXPHOS.

5. **Targeting OXPHOS as a Therapeutic Strategy:** The study suggests that targeting EGR1-mediated metabolic reprogramming to OXPHOS can overcome ibrutinib resistance. Metformin and IM156, an OXPHOS inhibitor, were used to inhibit the growth of ibrutinib-resistant lymphoma cells in vitro and in a mouse model derived from patient samples.

6. **Therapeutic Implications:** The findings propose a potential therapeutic strategy for overcoming ibrutinib resistance in relapsed/refractory DLBCL or MCL by targeting the EGR1-mediated metabolic pathway with agents like metformin or IM156.

In summary, the study uncovers a molecular mechanism involving EGR1 and metabolic reprogramming that contributes to ibrutinib resistance. Targeting this pathway with specific inhibitors offers a promising approach to improving outcomes for patients with relapsed or refractory DLBCL or MCL.

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S9604	Lixumistat (IM156)	Lixumistat (IM156), is a potent activator of AMPK that increases AMPK phosphorylation. IM156 blocks oxidative phosphorylation (OXPHOS) through the inhibition of complex I and increases apoptosis. IM156 ameliorates various types of fibrosis and inhibits tumors.

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AMPK Apoptosis related OXPHOS