多发性骨髓瘤（MM）是一种不可治愈的浆细胞恶性肿瘤，约占所有癌症的1％。尽管近年来在MM治疗方面取得了进展，由于蛋白酶体抑制剂（PIs）如硼替佐米（BTZ）和卡非佐米（CFZ）的引入，复发和疾病进展仍然很常见。因此，一个重要挑战是开发新的治疗方法以克服药物耐药性，改善患者预后，并扩大PIs对其他病理学的适用性。我们进行了基因和药物筛选，以确定与PIs有新的合成致死伴侣，并验证在PI敏感和耐药性MM细胞中的候选人。我们还在其他B细胞恶性肿瘤（如边缘区淋巴肿瘤，布基特淋巴瘤和弥漫大B细胞淋巴瘤）中测试了最佳的合成致死相互作用。我们在正常外周血单个核细胞（PBMCs）和骨髓基质细胞（BMSCs）中评估了联合治疗的毒性。我们在MM患者的原发性CD138 +细胞和不同的MM异种移植模型中确认了组合治疗的协同作用。我们利用RNA测序和逆向蛋白质组学（RPPA）研究了协同作用的分子机制。我们确定赖氨酸特异性去甲基化酶1（LSD1）作为一种顶级候选人，其抑制可以与CFZ治疗协同作用。LSD1沉默增强了PI耐药和PI敏感MM细胞对CFZ的敏感性，导致肿瘤细胞死亡增加。几种LSD1抑制剂（SP2509，SP2577和CC-90011）与不同的PIs在MM和其他B细胞肿瘤中触发了协同细胞毒性。CFZ / SP2509治疗对PBMCs和BMSCs表现出有利的细胞毒性。我们确认了LSD1-蛋白酶体抑制剂在MM患者的原发性CD138 +细胞和MM异种移植模型中的临床潜力，导致肿瘤进展的抑制。DNA损伤应答（DDR）和增殖机制是CFZ / SP2509联合治疗对抗肿瘤作用最显著的途径。 本研究在临床前阶段证明了LSD1抑制可能提供一种有价值的策略，以增强MM患者PI敏感性和克服耐药性，并且该组合可能用于其他B细胞恶性肿瘤的治疗，从而扩大了该项目的治疗影响。© 2023. YUMED Inc.和BioMed Central Ltd.

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.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.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.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.© 2023. YUMED Inc. and BioMed Central Ltd.