Podsypanina Katrina, Politi Katerina, Beverly Levi J, Varmus Harold E
Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5242-7. doi: 10.1073/pnas.0801197105. Epub 2008 Mar 20.
Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two oncogenes remain dependent on the activity of a single oncogene. Deinduction of either oncogene individually, or both oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of Kras(G12D) in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and Kras(G12D) transgenes further improved survival. Disease relapse after deinduction of both oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTV-rtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of oncogenes and that targeted approaches will also benefit from combination therapies.
大多数（即便不是全部）癌症都是由多个基因发生促癌突变的细胞组成。尽管最近的证据显示了针对单一突变蛋白的疗法的益处，但对于由多个协同作用的癌基因诱导产生实验性肿瘤的情况，却很少有人关注。利用在小鼠乳腺中表达的强力霉素诱导型和组成型Myc及突变型Kras转基因的组合，我们发现由两个癌基因协同作用诱导产生的肿瘤仍然依赖于单个癌基因的活性。单独去除任一癌基因，或同时去除两个癌基因，都会导致肿瘤部分或完全消退。在持续表达Myc的情况下去除Kras(G12D)后会出现长时间缓解，去除MYC转基因并持续表达突变型Kras对延长寿命有适度影响，而同时去除MYC和Kras(G12D)转基因则进一步提高了生存率。去除两个癌基因后疾病复发与所有复发性肿瘤中两个致癌转基因的重新激活有关，通常还伴有四环素反式激活因子转基因MMTV-rtTA中的继发性体细胞突变，使基因表达变得不依赖强力霉素。这些结果表明，癌基因组合中的每个基因都维持着肿瘤的生存能力，而且靶向治疗方法也将从联合疗法中受益。
