我們都知道癌癥在目前來(lái)說(shuō)是很難治愈的,，而這與癌細(xì)胞的抗藥性存在很大關(guān)系，其已成為癌癥治療的一大瓶頸,。據(jù)美國(guó)《每日科學(xué)》網(wǎng)站近日?qǐng)?bào)道,，美國(guó)研究人員已發(fā)現(xiàn)黑素瘤癌細(xì)胞的抗藥性機(jī)理，其可為解決這一難題指明方向,。
美國(guó)加州大學(xué)洛杉磯分校瓊森綜合癌癥研究中心的研究人員在一項(xiàng)臨床試驗(yàn)中發(fā)現(xiàn),，一種名為PLX4032的試驗(yàn)藥物對(duì)因BRAF基因發(fā)生突變而患上黑素瘤的癌癥患者非常有效。但這種療效持續(xù)的時(shí)間非常短,，平均只有7到9個(gè)月,，因?yàn)楸M管PLX4032定位了50%到60%的黑素瘤患者的BRAF變異，但是癌細(xì)胞會(huì)繞開它建立起來(lái)的封鎖,。
該研究的資深作者,、皮膚病學(xué)助理教授羅杰博士解釋說(shuō)，在一些病例中,，他發(fā)現(xiàn)當(dāng)PLX4032阻止了BRAF的存活途徑后,，癌細(xì)胞就開始超量表達(dá)一種細(xì)胞表面蛋白，創(chuàng)造出另一種生存途徑,；在其他病例中,，另一種致癌基因NRAS發(fā)生了變異，使得原本被PLX4032抑制的BRAF基因變異并發(fā)生了短路，這樣便再次激活了BRAF的存活通路,。由于PLX4032對(duì)NRAS沒有作用,，所以癌細(xì)胞就開始重新生長(zhǎng)了。
這項(xiàng)研究已發(fā)表在英國(guó)《自然》雜志上,。羅杰博士表示,，這項(xiàng)研究將引導(dǎo)對(duì)新的癌癥靶向療法的研發(fā)，以應(yīng)對(duì)病人出現(xiàn)癌癥抗藥性甚至復(fù)發(fā)的情況,。（生物谷Bioon.com）
生物谷推薦原文出處：
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: [email protected]
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.
