6月13日,，Nature雜志在線報道了結(jié)腸癌獲得性抵抗EGFR阻滯治療研究的重要進展。表達野生型KRAS蛋白的結(jié)腸癌細胞往往對EGFR阻斷治療敏感,。但在該治療開始幾個月后，幾乎都發(fā)生抵抗性,。對獲得性抗EGFR抗體抵抗的機制尚不清楚,。這種情況與某些小分子靶向治療藥物的情況大相徑庭。比如,，在ABL,、EGFR、BRAF和MEK等蛋白的編碼基因突變時,，才會出現(xiàn)針對其相應(yīng)抑制劑的治療抵抗,。
關(guān)于對EGFR阻斷治療出現(xiàn)抵抗這一異常現(xiàn)象,，最簡單的假說是：在這些表面上表達野生型KRAS的腫瘤組織中,，實際預(yù)先存在少量KRAS突變的腫瘤細胞。盡管這一假說似乎容易證明,，但卻既沒有臨床前模型的證據(jù),，也沒有來自患者的數(shù)據(jù)。
本研究試圖證實,，在給予抗EGFR抗體panitumumab治療的28名患者的循環(huán)血中是否可檢測到突變型KRAS的DNA,。結(jié)果發(fā)現(xiàn)，在24名治療前KRAS為野生型的患者中有9名（38%）患者的血清檢測出突變型KRAS,。其中3名的突變?yōu)槎辔稽c的不同突變,。這些突變的出現(xiàn)是持續(xù)性的，常在治療后5到6個月出現(xiàn),。數(shù)學(xué)模型提示,，這些突變出現(xiàn)在panitumumab治療起始前擴大的亞克隆群落中。
這些發(fā)現(xiàn)提示,，KRAS的突變是獲得性EGFR阻滯治療抵抗的媒介,；而且，這些突變可以用非侵入的方法檢測到,。這解釋了為什么實體瘤可以高度可重復(fù)的方式發(fā)生對靶向性治療的抵抗,。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers
Luis A. Diaz Jr,1, 2 Richard T. Williams,3 Jian Wu,1, 4 Isaac Kinde,1 J. Randolph Hecht,5 Jordan Berlin,6 Benjamin Allen,7 Ivana Bozic,7 Johannes G. Reiter,7, 8 Martin A. Nowak,7 Kenneth W. Kinzler,1 Kelly S. Oliner3 & Bert Vogelstein1
Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy1, 2. The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs3, 4, 5, 6. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6?months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.
