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Nature:药物治疗可造成肿瘤适应性进化

来源:生物谷 2015-02-13 12:46

                                                                    

2015年2月13日讯  /生物谷BIOON/  --近日,来自美国的科学家在著名国际期刊nature发表了一项最新研究成果,他们通过对进行了PI(3)Kα抑制剂BYL719治疗的肿瘤转移病人进行基因测序,发现PTEN在基因组中的变化会导致肿瘤细胞出现对BYL719的抵抗作用。这项研究为临床应用PI(3)Kα抑制剂治疗肿瘤提供了重要参考价值。
 
大范围深度的肿瘤基因组测序已经发现肿瘤异质性特点,并为不同肿瘤细胞克隆的转移进化特性提供了重要见解。但在另一个层面上,肿瘤进化可能受到治疗方法的选择压力,类似于在感染性疾病方面发生的情况。研究人员对一名携带PIK3CA基因突变并发生肿瘤转移的乳腺癌病人的肿瘤基因组进化情况进行了研究。
 
他们发现这名病人进行了PI(3)Kα抑制剂BYL719治疗后,获得了比较持久的治疗效果,但随后发现这名病人在进化上对该药物产生了抵抗作用(出现肺转移)并在很短时间内死亡。病人死后进行了快速的尸体解剖,并对其14个肿瘤转移位点进行了组织取材和测序。与治疗前的肿瘤相比,所有转移病变位置均出现PTEN基因拷贝丢失,那些对BYL719产生抵抗的病变位点还出现了额外的与原拷贝不同的PTEN基因变化,从而导致PTEN表达缺失。
 
研究人员还检测了另外六名进行BYL719治疗的病人,在其中一名病人中发现PTEN双等位基因缺失,而在另外两名病人的原发肿瘤中发现的PIK3CA突变在研究进展过程中已经检测不到。为了在功能上描述这些发现,研究人员在临床前模型(对BYL719敏感的细胞系和PTEN缺失的异种移植组织)检测了PTEN敲低所造成的影响,结果发现均出现对BYL719的抵抗,但同时阻断PI(3)Kp100β的作用能够逆转这一抵抗表型的出现。
 
研究人员总结到携带不同PTEN基因组变化的不同转移部位发生并行遗传进化,导致了PTEN缺失的肿瘤对PI(3)Kα抑制产生渐行抵抗作用。这项研究为解决临床应用PI(3)Kα抑制剂治疗肿瘤出现的药物抵抗问题提供了新的见解。(生物谷Bioon.com)
 
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Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor
 
Dejan Juric,1, n1Pau Castel,2, n1Malachi Griffith,3, 4, 5, Obi L. Griffith,4, 5, 6, Helen H. Won,2, 7, Haley Ellis,2, Saya H. Ebbesen,8, Benjamin J. Ainscough,5, Avinash Ramu,5, Gopa Iyer,2, 9, Ronak H. Shah,2, Tiffany Huynh,1, Mari Mino-Kenudson,1, Dennis Sgroi,1, Steven Isakoff,1, Ashraf Thabet,1, Leila Elamine,1, David B. Solit,2, 9, Scott W. Lowe,8, 10, Cornelia Quadt,11, Malte Peters,11, Adnan Derti,12, Robert Schegel,12, Alan Huang,12, Elaine R. Mardis,3, 4, 5, 6, Michael F. Berger,2, 7, José Baselga2, 13, & Maurizio Scaltriti2,
 
Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones1, 2. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110β blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.
 
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