Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA.
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Cancer Lett. 2023 Aug 1;568:216284. doi: 10.1016/j.canlet.2023.216284. Epub 2023 Jun 24.
Drug resistance and disease progression are common in multiple myeloma (MM) patients, underscoring the need for new therapeutic combinations. A high-throughput drug screen in 47 MM cell lines and in silico Huber robust regression analysis of drug responses revealed 43 potentially synergistic combinations. We hypothesized that effective combinations would reduce MYC expression and enhance p16 activity. Six combinations cooperatively reduced MYC protein, frequently over-expressed in MM and also cooperatively increased p16 expression, frequently downregulated in MM. Synergistic reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines, while sparing fibroblasts. Three combinations significantly prolonged survival in a transplantable Ras-driven allograft model of advanced MM closely recapitulating high-risk/refractory myeloma in humans and reduced viability of ex vivo treated patient cells. Common genetic pathways similarly downregulated by these combinations promoted cell cycle transition, whereas pathways most upregulated were involved in TGFβ/SMAD signaling. These preclinical data identify potentially useful drug combinations for evaluation in drug-resistant MM and reveal potential mechanisms of combined drug sensitivity.
耐药性和疾病进展在多发性骨髓瘤（MM）患者中很常见，这凸显了新的治疗联合方案的必要性。在 47 种 MM 细胞系中进行高通量药物筛选，并对药物反应进行 Huber 稳健回归分析，揭示了 43 种潜在的协同组合。我们假设有效的组合将降低 MYC 表达并增强 p16 活性。六种组合协同降低了 MM 中经常过表达的 MYC 蛋白，并且经常下调 MM 中的 p16 表达。在蛋白酶体抑制剂耐药和敏感的 MM 细胞系中，观察到具有最高协同作用的组合可协同降低细胞活力，同时保留成纤维细胞。三种组合在移植的 Ras 驱动的同种异体移植模型中显著延长了晚期 MM 的存活时间，该模型非常类似于人类的高危/难治性骨髓瘤，并降低了体外处理的患者细胞的活力。这些组合共同下调的常见遗传途径促进细胞周期过渡，而上调最多的途径则参与 TGFβ/SMAD 信号传导。这些临床前数据确定了可能对耐药性 MM 进行评估的有用药物组合，并揭示了联合药物敏感性的潜在机制。
