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Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

机译：大肠癌中KRAS突变的出现和对抗EGFR治疗的获得性耐药

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摘要

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers~1. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug2. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood~(3-8). Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.%本期Nature上两篇论文表明，K．Ras突变在临床抗药性／复发出现之前可以在患者血清中检测到。使用以“表皮生长因子受体”(EGFR)为目标的抗体，已成为治疗结肠直肠癌的一种成熟方法，但它们不能用于KRAS致癌基因上携带突变的患者。抗药性还会在最初有疗效的患者身上出现。本期Nature上两篇论文提出的明rn确证据表明，KRAS基因的突变是造成很多患者对“抗-EGFR抗体”产生获得性抗药性的原因。Misale等人通过细胞系模型发现，KRAS突变会造成对“西妥昔单抗”(cetuximab)的抗药性。在用“西妥昔单抗”或“帕尼单抗”治疗的结肠直肠癌患者中，抗药性与从事先存在的亚克隆选择的KRAS突变有关或是在治疗过程中获得的。D{az等人还发现，KRAS突变在对“帕尼单抗”有抗药性的患者中会积累。他们的数学模型表明，KRAS突变在治疗之前存在于肿瘤细胞中，这也许可以解释为什么临床复发通常是在治疗开始大约六个月后发现的——到这个时候，有抗药性的、携带KRAS突变的肿瘤细胞亚组就会扩大。这种明显无法避免的抗药性表明，如果要避免抗药性，将需要以一个以上致癌通道为目标的药物组合。
机译：选择性靶向激酶信号通路的疗法的主要局限性是继发性耐药的出现。西妥昔单抗是一种结合表皮生长因子受体（EGFR）胞外域的单克隆抗体，可有效治疗KRAS野生型转移性结直肠癌〜1。在最初的反应后，继发的继发耐药性必然随之而来，从而限制了该药物的临床获益。人们对大肠癌中西妥昔单抗继发性耐药的分子基础了解甚少（3-8）。在这里，我们表明，KRAS的分子改变（在大多数情况下是点突变）与大肠癌中抗EGFR治疗获得性耐药的发生有因果关系。在其内源基因启动子的控制下，突变KRAS的表达足以赋予西妥昔单抗耐药性，但耐药细胞对EGFR和促分裂原活化蛋白激酶（MEK）的组合抑制仍然敏感。对西妥昔单抗或帕尼单抗产生抗药性的患者的转移分析表明，在一个样品中出现了KRAS扩增，在60％的病例中（10个中有6个）获得了继发性KRAS突变。早在影像学记录疾病进展之前，就已经在接受西妥昔单抗治疗的患者血液中检测到KRAS突变等位基因。总而言之，这些结果确定了KRAS突变是结直肠癌中对西妥昔单抗获得性耐药的常见驱动因素，表明可以在放射学进展前数月无创检测KRAS突变克隆的出现，并建议尽早开始使用MEK抑制剂作为合理策略。 ％本期自然上两篇论文表明，K．Ras突变在临床抗药性/复发出现之前可以在患者血清中检测到。使用以“表皮生长因子受体”（EGFR）为目标的抗体，已成为治疗结肠直肠癌的一种成熟方法，但它们不能用于KRAS致癌基因上转移突变的患者。抗药性发生在最初有治愈的患者身上出现。本期性质上两篇论文提出的明rn确证证据表明，KRAS基因的突变是造成很多患者对“抗-EGFR抗体”产生性抗药性的原因的。Misale等人通过细胞系模型发现，KRAS突变会造成对“西妥昔单在用“西妥昔单抗”或“帕尼单抗”治疗的结肠直肠癌患者中，抗药性与从已有的亚克隆选择的KRAS突变有关或在D {az等人还发现，KRAS突变在对“帕尼单抗”有抗药性的患者中会积累。他们的数学模型表明，KRAS突变在治疗之前存在于肿瘤细胞中，这也许可以解释为什么临床复发通常是在治疗开始大约六个月后发现的-到这个时候，有抗药性的，携带KRAS突变的肿瘤细胞亚组就会扩大。这种明显无法避免的抗药性例如，如果要避免抗药性，将需要以一个以上致癌通道为目标的药物组合。

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  • 来源
    《Nature》 |2012年第7404期|p.532-536a1-a2|共7页
  • 作者

    Sandra Misale; RonaYaeger; Sebastijan Hobor; Elisa Scala; Manickam Janakiraman; David Liska; Emanuele Valtorta; Roberta Schiavo; Michela Buscarino; Giulia Siravegna; Katia Bencardino; Andrea Cercek; Chin-Tung Chen; Silvio Veronese; Carlo Zanon; Andrea Sartore-Bianchi; Marcello Gambacorta; Margherita Gallicchio; Efsevia Vakiani; Valentina Boscaro; Enzo Medico; Martin Weiser; Salvatore Siena; Federica Di Nicolantonio; David Solit; Alberto Bardelli;

  • 作者单位

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy.Department of Oncological Sciences, University of Torino Medical School, 10060 Candiolo (Torino), Italy;

    Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy;

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy.Department of Oncological Sciences, University of Torino Medical School, 10060 Candiolo (Torino), Italy;

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Department of Surgery, Memorial Sloan-KetteringCancer Center, New York, New York 10065, USA;

    Division of Pathology, Ospedale Niguarda Ca' Granda.20162 Milano, Italy;

    Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, 20162 Milano, Italy;

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy.Department of Oncological Sciences, University of Torino Medical School, 10060 Candiolo (Torino), Italy;

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy;

    Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, 20162 Milano, Italy;

    Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Department of Surgery, Memorial Sloan-KetteringCancer Center, New York, New York 10065, USA;

    Division of Pathology, Ospedale Niguarda Ca' Granda.20162 Milano, Italy;

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy;

    Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, 20162 Milano, Italy;

    Division of Pathology, Ospedale Niguarda Ca' Granda.20162 Milano, Italy;

    Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, 10125 Torino, Italy;

    Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, 10125 Torino, Italy;

    Department of Oncological Sciences, University of Torino Medical School, 10060 Candiolo (Torino), Italy.Laboratory of Functional Genomics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy;

    Department of Surgery, Memorial Sloan-KetteringCancer Center, New York, New York 10065, USA;

    Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, 20162 Milano, Italy;

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy.FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy;

    Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (Torino), Italy.Department of Oncological Sciences, University of Torino Medical School, 10060 Candiolo (Torino), Italy.FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy;

  • 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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