Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain.
Cancer Cell. 2010 Jul 13;18(1):63-73. doi: 10.1016/j.ccr.2010.05.025.
We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates human non-small cell lung carcinoma (NSCLC). Ablation of Cdk4, but not Cdk2 or Cdk6, induces an immediate senescence response only in lung cells that express an endogenous K-Ras oncogene. No such response occurs in lungs expressing a single Cdk4 allele or in other K-Ras-expressing tissues. More importantly, targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression. These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes.
我们在一个能高度模拟人类非小细胞肺癌（NSCLC）的小鼠肿瘤模型中发现了 K-Ras 癌基因和 Cdk4 之间的合成致死相互作用。仅在表达内源性 K-Ras 癌基因的肺细胞中，Cdk4 的缺失而非 Cdk2 或 Cdk6 的缺失会立即诱导衰老反应。在表达单个 Cdk4 等位基因或其他表达 K-Ras 的组织中，不会发生这种反应。更重要的是，针对 CT 扫描可检测到的晚期肿瘤中的 Cdk4 等位基因，也会诱导衰老并阻止肿瘤进展。这些观察结果表明，对携带 K-RAS 癌基因的 NSCLC 患者进行强有力和选择性的 Cdk4 药理学抑制可能会带来治疗益处。
