Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.
Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.
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通过单细胞测序鉴定复发性多发性骨髓瘤患者的耐药途径和治疗靶点。
DOI：
10.1038/s41591-021-01232-w
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发表时间：
2021-03
期刊：
影响因子：
82.9
通讯作者：
Amit I
中科院分区：
文献类型：
--
作者：
Cohen YC;Zada M;Wang SY;Bornstein C;David E;Moshe A;Li B;Shlomi-Loubaton S;Gatt ME;Gur C;Lavi N;Ganzel C;Luttwak E;Chubar E;Rouvio O;Vaxman I;Pasvolsky O;Ballan M;Tadmor T;Nemets A;Jarchowcky-Dolberg O;Shvetz O;Laiba M;Shpilberg O;Dally N;Avivi I;Weiner A;Amit I
多发性骨髓瘤（MM）是一种以恶性浆细胞克隆性增殖为特征的肿瘤性浆细胞疾病。尽管进行了广泛的研究，但耐药患者内部和之间的疾病异质性特征很差。在本研究中，我们进行了一项前瞻性、多中心、单臂临床试验（NCT 04065789），结合纵向单细胞RNA测序（scRNA-seq）研究MM耐药机制的分子动力学。新诊断的MM患者（41例）在接受含硼替佐米的诱导治疗方案后未能缓解或出现早期复发，入组研究以评估达雷妥尤单抗、卡非佐米、来那度胺和地塞米松联合治疗的安全性和疗效。主要临床终点是安全性和耐受性。次要终点包括总缓解率、无进展生存期和总生存期。治疗是安全的，耐受性良好;实现了深度和持久的反应。在预先规定的探索性分析中，将41例原发性难治性和早期复发患者与11例健康受试者和15例新诊断的MM患者进行比较，发现了新的MM耐药分子途径，包括缺氧耐受性、蛋白质折叠和线粒体呼吸，这推广到更大的临床队列（CoMMpass）。我们发现肽基脯氨酰异构酶A（PPIA）（蛋白质折叠反应途径中的中心酶）作为耐药性MM的潜在新靶点。PPIA的CRISPR-Cas9缺失或用小分子抑制剂（环孢素）抑制PPIA显著使MM肿瘤细胞对蛋白酶体抑制剂敏感。总之，我们的研究定义了在临床试验中整合scRNA-seq的路线图，确定了高度耐药MM患者的特征，并发现PPIA是这些肿瘤的有效治疗靶点。
Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.
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DOI：
10.3816/clm.2009.n.056
发表时间：
2009-08
期刊：
Clinical lymphoma & myeloma
影响因子：
--
作者：
Kyle RA;Rajkumar SV
通讯作者：
Rajkumar SV
影响因子：
11.4
作者：
Kumar SK;Dispenzieri A;Fraser R;Mingwei F;Akpek G;Cornell R;Kharfan-Dabaja M;Freytes C;Hashmi S;Hildebrandt G;Holmberg L;Kyle R;Lazarus H;Lee C;Mikhael J;Nishihori T;Tay J;Usmani S;Vesole D;Vij R;Wirk B;Krishnan A;Gasparetto C;Mark T;Nieto Y;Hari P;D'Souza A
通讯作者：
D'Souza A
DOI：
10.1126/science.1247651
发表时间：
2014-02-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jaitin DA;Kenigsberg E;Keren-Shaul H;Elefant N;Paul F;Zaretsky I;Mildner A;Cohen N;Jung S;Tanay A;Amit I
通讯作者：
Amit I
影响因子：
45.3
作者：
Decaux, Olivier;Lode, Laurence;Minvielle, Stephane
通讯作者：
Minvielle, Stephane
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.