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首页> 外文期刊>Nature >Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma
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Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma

机译：黑色素瘤对BRAF（V600E）抑制的可逆和适应性耐药

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摘要

Treatment of BRAF( V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX 10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a (drug holiday* and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.
机译：用靶向BRAF或MEK激酶的小分子药物治疗BRAF（V600E）突变型黑色素瘤可能是有效的，但耐药性会不断发展。相反，由于表皮生长因子受体（EGFR）的反馈激活，具有相同BRAF（V600E）突变的结肠癌对BRAF抑制剂具有内在抗性。在这里，我们显示在对BRAF或MEK抑制剂产生耐药性后，分析的16个黑色素瘤中有6个获得了EGFR表达。使用针对染色质调节剂的短发夹RNA（shRNA）文库，我们发现黑色素瘤中性别决定区域Y-box 10（SOX10）的抑制导致TGF-β信号的激活，从而导致EGFR和血小板衍生的上调生长因子受体-β（PDGFRB），赋予对BRAF和MEK抑制剂的抗性。 EGFR在黑色素瘤中的表达或TGF-β的治疗导致表型缓慢增长，细胞表现出癌基因诱导的衰老特征。但是，在BRAF或MEK抑制剂存在下，EGFR表达或暴露于TGF-β有利于增殖。在具有不同SOX10抑制水平的黑色素瘤细胞的异质群体中，在药物存在下，具有低SOX10和因此高EGFR表达的细胞会迅速富集，但是在停止药物治疗时会逆转。我们在6个EGFR阳性耐药黑色素瘤患者样本中的4个样本中发现了SOX 10丢失和/或TGF-β信号激活的证据。我们的发现为为什么某些BRAF或MEK抑制剂耐药的黑色素瘤患者在（药物休假*之后）重新获得对这些药物的敏感性提供了依据，并将EGFR阳性黑色素瘤患者确定为可能受益于药物休假后重新治疗的人群。

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  • 来源
    《Nature》 |2014年第7494期|118-122|共5页
  • 作者

    Chong Sun; Liqin Wang; Sidong Huang; Guus J. J. E. Heynen; Anirudh Prahallad; Caroline Robert; John Haanen; Christian Blank; Jelle Wesseling; Stefan M. Willems; Davide Zecchin; Sebastijan Hobor; Prashanth K. Bajpe; Cor Lieftink; Christina Mateus; Stephan Vagner; Wipawadee Grernrum; Ingrid Hofland; Andreas Schlicker; Lodewyk F. A. Wessels; Roderick L. Beijersbergen; Alberto Bardelli; Federica Di Nicolantonio; Alexander M. M. Eggermont; Rene Bernards;

  • 作者单位

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands,Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    InstitutGustave Roussy, 114 Rue Edouard Vailtant, 94800 Villejuif, France;

    Division of Medical Oncology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherland, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Medical Oncology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherland, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Pathology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands,Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100,3584 CX, Utrecht, The Netherlands;

    University of Torino, Department of Oncology, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy,Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95,10060 Candiolo, Torino, Italy;

    Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95,10060 Candiolo, Torino, Italy;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    InstitutGustave Roussy, 114 Rue Edouard Vailtant, 94800 Villejuif, France;

    InstitutGustave Roussy, 114 Rue Edouard Vailtant, 94800 Villejuif, France;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Pathology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

    University of Torino, Department of Oncology, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy,Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95,10060 Candiolo, Torino, Italy,FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy;

    University of Torino, Department of Oncology, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy,Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95,10060 Candiolo, Torino, Italy;

    InstitutGustave Roussy, 114 Rue Edouard Vailtant, 94800 Villejuif, France;

    Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, The Netherlands;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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