加拿大瑪嘉烈醫(yī)院癌癥中心的臨床研究人員發(fā)現(xiàn),,未成熟祖細(xì)胞的耐藥性是導(dǎo)致多發(fā)性骨髓瘤復(fù)發(fā)的根本原因。此項研究成果發(fā)表在今天的《癌細(xì)胞》雜志網(wǎng)絡(luò)版上,。
研究表明,,使用蛋白酶抑制劑“萬珂”的主流療法可殺死組成大多數(shù)腫瘤的漿細(xì)胞,但其無法觸及祖細(xì)胞,。祖細(xì)胞增殖并成熟后,,即便是在病情似乎已得到完全緩解的情況下也會重啟疾病進(jìn)程。
瑪嘉烈醫(yī)院血液學(xué)家,、多倫多大學(xué)醫(yī)學(xué)院助理教授羅杰·泰德曼博士稱,,此項發(fā)現(xiàn)為治愈多發(fā)性骨髓瘤指明了一條新途徑,那就是同時將祖細(xì)胞和漿細(xì)胞作為治療靶標(biāo),。了解了祖細(xì)胞的耐藥性是導(dǎo)致多發(fā)性骨髓瘤“愈后”復(fù)發(fā)的主因,,醫(yī)生在臨床實踐中就可測出患者體內(nèi)的“殘存”病情,開發(fā)新藥或利用現(xiàn)有藥物進(jìn)行針對性治療,。
在研究多發(fā)性骨髓瘤治療失效的過程中,,研究人員發(fā)現(xiàn)了該種疾病與腫瘤細(xì)胞成熟度之間的關(guān)系,并證明了骨髓癌細(xì)胞的成熟度對蛋白酶抑制劑的敏感性起著重要作用,。目前的藥物研究專注于開發(fā)新的蛋白酶抑制劑,,僅沿著此一路徑將永遠(yuǎn)無法治愈多發(fā)性骨髓瘤。
泰德曼表示,,如果將多發(fā)性骨髓瘤比作雜草,,類似“萬珂”這樣的蛋白酶抑制劑就像是愛挑剔的山羊,它只吃地面上的成熟葉子,,地面的雜草雖沒有了,,但由于沒有吃到草根,因此一段時間以后雜草還會長出來,。
研究人員對7500個多發(fā)性骨髓瘤細(xì)胞進(jìn)行了高通量篩選試驗,,并觀察其藥物反應(yīng)效果,,然后對患者進(jìn)行骨髓活檢以進(jìn)一步確定藥效。試驗最終發(fā)現(xiàn)有兩個基因(IRE1和XBP1)可調(diào)整對蛋白酶抑制劑“萬珂”的反應(yīng),,從而明確了作為治愈障礙的耐藥性背后的作用機理,。(生物谷 Bioon.com)
生物谷推薦的英文摘要
Cancer Cell Doi:10.1016/j.ccr.2013.08.009
Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma
Chungyee Leung-Hagesteijn, Natalie Erdmann, Grace Cheung, Jonathan J. Keats, A. Keith Stewart, Donna E. Reece, Kim Chan Chung, Rodger E. Tiedemann
Highlights
MM tumors contain Xbp1s− progenitors that survive proteasome inhibition
Xbp1s absence arrests secretory maturation and ER loading, reducing ERAD dependence
PI resistance mechanisms in patients differ from in vitro models
These data help explain the failure to cure MM with current therapy
Summary
Proteasome inhibitor (PI) resistance mechanisms in multiple myeloma (MM) remain controversial. We report the existence of a progenitor organization in primary MM that recapitulates maturation stages between B cells and plasma cells and that contributes to clinical PI resistance. Xbp1s− tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation arrest of MM before the plasmablast stage enables progressive disease on PI treatment. Mechanistically, suppression of Xbp1s in MM is shown to induce bortezomib resistance via de-commitment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation. These results reveal the tumor progenitor structure in MM and highlight its role in therapeutic failure.