Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.
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DOI：
10.1038/nature11156
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发表时间：
2012-06-28
期刊：
影响因子：
64.8
通讯作者：
Bardelli, Alberto
中科院分区：
文献类型：
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作者：
Misale, Sandra;Yaeger, Rona;Hobor, Sebastijan;Scala, Elisa;Janakiraman, Manickam;Liska, David;Valtorta, Emanuele;Schiavo, Roberta;Buscarino, Michela;Siravegna, Giulia;Bencardino, Katia;Cercek, Andrea;Chen, Chin-Tung;Veronese, Silvio;Zanon, Carlo;Sartore-Bianchi, Andrea;Gambacorta, Marcello;Gallicchio, Margherita;Vakiani, Efsevia;Boscaro, Valentina;Medico, Enzo;Weiser, Martin;Siena, Salvatore;Di Nicolantonio, Federica;Solit, David;Bardelli, Alberto
选择性靶向激酶信号通路的治疗的一个主要限制是继发性耐药的出现。西妥昔单抗是一种结合EGFR细胞外结构域的单克隆抗体，对KRAS野生型转移性结直肠癌的一个亚群有效。在最初的反应之后，继发性耐药总是随之而来，从而限制了这种药物的临床获益。结直肠癌西妥昔单抗继发耐药的分子基础尚不清楚。在这里，我们首次表明KRAS的分子改变（在大多数情况下是点突变）与结直肠癌中抗egfr治疗获得性耐药的发生有因果关系。在其内源性基因启动子的控制下，KRAS突变体的表达足以赋予西妥昔单抗耐药性，但耐药细胞仍然对EGFR和MEK的联合抑制敏感。对西妥昔单抗或帕尼单抗耐药患者的转移分析显示，在一个样本中出现KRAS扩增，60%（6/10）的病例获得继发性KRAS突变。KRAS突变等位基因在西妥昔单抗治疗患者的血液中可检测到，早在x线摄影记录疾病进展前10个月。总之，研究结果确定KRAS突变是结直肠癌患者获得性西妥昔单抗耐药的常见驱动因素，表明KRAS突变克隆的出现可以在放射学进展前几个月无创检测到，并建议早期启动MEK抑制剂作为延迟或逆转耐药的合理策略。
A main limitation of therapies that selectively target kinase signaling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of EGFR, is effective in a subset of KRAS wild type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here, we show for the first time 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 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% (6/10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab treated patients as early as 10 months prior to 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 prior to radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.
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影响因子：
3.7
作者：
Hatakeyama H;Cheng H;Wirth P;Counsell A;Marcrom SR;Wood CB;Pohlmann PR;Gilbert J;Murphy B;Yarbrough WG;Wheeler DL;Harari PM;Guo Y;Shyr Y;Slebos RJ;Chung CH
通讯作者：
Chung CH
DOI：
10.1158/1078-0432.ccr-10-2277
发表时间：
2011-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arcila ME;Oxnard GR;Nafa K;Riely GJ;Solomon SB;Zakowski MF;Kris MG;Pao W;Miller VA;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
51.1
作者：
Moroni, M;Veronese, S;Bardelli, A
通讯作者：
Bardelli, A
影响因子：
8.8
作者：
Smith, G.;Bounds, R.;Wolf, C. R.
通讯作者：
Wolf, C. R.
DOI：
10.1073/pnas.0808757105
发表时间：
2008-12-30
影响因子：
11.1
作者：
Di Nicolantonio, Federica;Arena, Sabrina;Bardelli, Alberto
通讯作者：
Bardelli, Alberto