我们都知道癌症在目前来说是很难治愈的，而这与癌细胞的抗药性存在很大关系，其已成为癌症治疗的一大瓶颈。据美国《每日科学》网站近日报道，美国研究人员已发现黑素瘤癌细胞的抗药性机理，其可为解决这一难题指明方向。
美国加州大学洛杉矶分校琼森综合癌症研究中心的研究人员在一项临床试验中发现，一种名为PLX4032的试验药物对因BRAF基因发生突变而患上黑素瘤的癌症患者非常有效。但这种疗效持续的时间非常短，平均只有7到9个月，因为尽管PLX4032定位了50%到60%的黑素瘤患者的BRAF变异，但是癌细胞会绕开它建立起来的封锁。
该研究的资深作者、皮肤病学助理教授罗杰博士解释说，在一些病例中，他发现当PLX4032阻止了BRAF的存活途径后，癌细胞就开始超量表达一种细胞表面蛋白，创造出另一种生存途径；在其他病例中，另一种致癌基因NRAS发生了变异，使得原本被PLX4032抑制的BRAF基因变异并发生了短路，这样便再次激活了BRAF的存活通路。由于PLX4032对NRAS没有作用，所以癌细胞就开始重新生长了。
这项研究已发表在英国《自然》杂志上。罗杰博士表示，这项研究将引导对新的癌症靶向疗法的研发，以应对病人出现癌症抗药性甚至复发的情况。（生物谷Bioon.com）
生物谷推荐原文出处：
Nature 24 November 2010 | doi:10.1038/nature09626
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
Ramin Nazarian1,2,9, Hubing Shi1,2,9, Qi Wang1,2, Xiangju Kong1,2, Richard C. Koya2,3, Hane Lee2,4, Zugen Chen2,4, Mi-Kyung Lee1,2, Narsis Attar2,5, Hooman Sazegar2,5, Thinle Chodon2,5, Stanley F. Nelson2,4,6, Grant McArthur7, Jeffrey A. Sosman8, Antoni Ribas2,3,5 & Roger S. Lo1,2
Division of Dermatology/Department of Medicine, UCLA’s Jonsson Comprehensive Cancer Center, 52-121 CHS, Los Angeles, California 90095-1750, USA
David Geffen School of Medicine, University of California, Los Angeles, California 90095-1750, USA
Division of Surgical Oncology/Department of Surgery, UCLA’s Jonsson Comprehensive Cancer Center, 54-140 CHS, Los Angeles, California 90095-1782, USA
Department of Human Genetics, UCLA’s Jonsson Comprehensive Cancer Center, 5506A Gonda Center, Los Angeles, California 90095-7088, USA
Division of Hematology & Oncology/Department of Medicine, UCLA’s Jonsson Comprehensive Cancer Center, 9-954 Factor Building, Los Angeles, California 90095-1678, USA
Department of Pediatrics, UCLA’s Jonsson Comprehensive Cancer Center, 5506A Gonda Center, Los Angeles, California 90095-7088, USA
Peter MacCallum Cancer Center, St Andrews Place, East Melbourne 3002, Australia
Department of Medicine, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, Tennessee 37232-6838, USA
These authors contributed equally to this work.
Correspondence to: Roger S. Lo1,2 Email: rlo@mednet.ucla.edu
Abstract
Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ~7% of human malignancies and ~60% of melanomas1. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses2. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways3, 4, 5. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
