Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma

by Selleckchem | Nov 20 2023

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 1% of all cancers. Despite recent advances in the treatment of MM, due to the introduction of proteasome inhibitors (PIs) such as bortezomib (BTZ) and carfilzomib (CFZ), relapses and disease progression remain common. Therefore, a major challenge is the development of novel therapeutic approaches to overcome drug resistance, improve patient outcomes, and broaden PIs applicability to other pathologies.

Methods: We performed genetic and drug screens to identify new synthetic lethal partners to PIs, and validated candidates in PI-sensitive and -resistant MM cells. We also tested best synthetic lethal interactions in other B-cell malignancies, such as mantle cell, Burkitt's and diffuse large B-cell lymphomas. We evaluated the toxicity of combination treatments in normal peripheral blood mononuclear cells (PBMCs) and bone marrow stromal cells (BMSCs). We confirmed the combo treatment' synergistic effects ex vivo in primary CD138+ cells from MM patients, and in different MM xenograft models. We exploited RNA-sequencing and Reverse-Phase Protein Arrays (RPPA) to investigate the molecular mechanisms of the synergy.

Results: We identified lysine (K)-specific demethylase 1 (LSD1) as a top candidate whose inhibition can synergize with CFZ treatment. LSD1 silencing enhanced CFZ sensitivity in both PI-resistant and -sensitive MM cells, resulting in increased tumor cell death. Several LSD1 inhibitors (SP2509, SP2577, and CC-90011) triggered synergistic cytotoxicity in combination with different PIs in MM and other B-cell neoplasms. CFZ/SP2509 treatment exhibited a favorable cytotoxicity profile toward PBMCs and BMSCs. We confirmed the clinical potential of LSD1-proteasome inhibition in primary CD138+ cells of MM patients, and in MM xenograft models, leading to the inhibition of tumor progression. DNA damage response (DDR) and proliferation machinery were the most affected pathways by CFZ/SP2509 combo treatment, responsible for the anti-tumoral effects.

Conclusions: The present study preclinically demonstrated that LSD1 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients and that this combination might be exploited for the treatment of other B-cell malignancies, thus extending the therapeutic impact of the project.

Comments:

The findings from your study are indeed promising and have significant implications for the treatment of multiple myeloma (MM) and other B-cell malignancies. The identification of lysine-specific demethylase 1 (LSD1) as a synthetic lethal partner to proteasome inhibitors (PIs) such as carfilzomib (CFZ) suggests a novel therapeutic approach to enhance PI sensitivity and overcome drug resistance in MM patients.

The key points from your study include:

1. **Identification of LSD1 as a Synthetic Lethal Partner:** LSD1 inhibition was identified as a strategy to synergize with CFZ treatment, enhancing its sensitivity in both PI-resistant and -sensitive MM cells. This highlights LSD1 as a potential target for combination therapy.

2. **Efficacy Across B-cell Malignancies:** The study demonstrated the efficacy of LSD1 inhibition in combination with PIs not only in MM but also in other B-cell malignancies, including mantle cell lymphoma, Burkitt's lymphoma, and diffuse large B-cell lymphoma. This suggests a broader applicability of the combination therapy approach.

3. **Safety and Clinical Potential:** The combination of CFZ and LSD1 inhibitors exhibited favorable cytotoxicity profiles in normal peripheral blood mononuclear cells (PBMCs) and bone marrow stromal cells (BMSCs). Additionally, the clinical potential of LSD1-proteasome inhibition was confirmed in primary CD138+ cells from MM patients and MM xenograft models, inhibiting tumor progression.

4. **Mechanistic Insights:** RNA-sequencing and Reverse-Phase Protein Arrays (RPPA) were employed to investigate the molecular mechanisms underlying the synergistic effects. The study revealed that the DNA damage response (DDR) and proliferation machinery were significantly affected pathways, contributing to the anti-tumoral effects of the CFZ/SP2509 combination treatment.

5. **Therapeutic Implications:** The study's findings suggest that LSD1 inhibition could be a valuable strategy to enhance PI sensitivity, potentially leading to improved outcomes for MM patients. Moreover, the extension of this approach to other B-cell malignancies could broaden its therapeutic impact.

In summary, your research provides preclinical evidence supporting the combination of LSD1 inhibitors with proteasome inhibitors as a promising therapeutic strategy for MM and other related B-cell malignancies. Further clinical studies and trials will be essential to validate these findings in patients and to assess the long-term efficacy and safety of this combination therapy.