黑素瘤对新药组合疗法产生耐药性的分子机制

  近日，来自加利福利亚大学洛杉矶分校Jonsson综合癌症中心的研究人员揭示了黑色素瘤对当前新型药物组合疗法产生耐药性的分子机制，这种新型疗法是一种利用BRAF+MEK抑制剂对黑色素瘤患者进行治疗的最新组合疗法。

  在这项最新为期两年时间的研究里，研究者Lo及其同事分别在患者进行BRAF+MEK抑制剂组合药物疗法前，以及黑色素瘤产生耐药性导致疗法失效后，对15名患者的43份肿瘤样本进行了研究；这些参与者在开始治疗时均受益于组合疗法，但是治疗一段时间后肿瘤就会死灰复燃。

  研究者从所有的肿瘤活检样本中提取了遗传物质进行深度分析研究，随后研究者发现，黑色素瘤细胞可以重新规划其生长回路，从而绕过药物组合的抑制作用。Lo表示，黑色素瘤细胞可以通过在关键的致癌基因中产生高度罕见的遗传改变，从而实现抵御BRAF+MEK抑制剂疗法的目的。当前我们需要寻找可以超越BRAF+MEK抑制剂疗法的新方法，要么寻找新型的靶向药物，要么对当前的药物组合进行改变，但最终目的就是在黑色素瘤耐药性增强之前将其杀灭。

  在很多病例中，黑色素瘤往往会变得非常耐受，如今研究者们希望更为深入地理解癌细胞产生耐药性的分子机制，这或许可以帮助他们开发新型的疗法。据估计在美国每年大约有7万名新发黑色素瘤病人，而其中每年有8000人因该疾病而死亡，大约50%的患者会发展成为转移性的黑色素瘤，或者每年有大约4000名患者机体中产生一种BRAF的突变。

  最后研究者表示，如果我们可以理解疾病如何对抗疗法，那么我们或许可以开始设计新型更有效地疗法来有效治疗疾病。（转化医学网360zhyx.com）
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During the new two-year study, Lo and his team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitor combo drugs and then after they relapsed due to the melanoma developing drug resistance. The participants had all benefited from the combo therapy initially, but after periods of time the tumors regressed.
All the tumors biopsied from the patients were subjected to in-depth analysis of the genetic material extracted from the tumors. This analysis of patient-derived tumors then provided leads for the investigators to study how melanoma cells grown in Lo's laboratory rewired their growth circuitry to get around the combo inhibitors.
Lo's team found that the melanoma cells resist the combo therapy of BRAF+MEK inhibitors by developing highly unusual genetic changes in certain key cancer genes. These signature genetic changes or configurations not only mark the presence of drug resistance melanoma cells but also tell us about potential new ways to shut them off.
"We need to find ways to go beyond the BRAF+MEK drug combination, by possibly finding a third drug, or alter how we prescribe the combo of drugs," said Lo, UCLA assistant professor of dermatology. "The idea is to eventual suppress melanoma drug resistance even before it arises."
"In most cases, melanoma eventually becomes resistant," said Dr. Antoni Ribas, JCCC member and professor of hematology and oncology, and a co-author of the study. "We now understand the molecular basis of the resistance mechanisms, which leads to the planning of new treatment approaches to disable these mechanisms."