Authors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Authors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, GermanyAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, GermanyAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical F
Cancer Res. 2014 May 15;74(10):2825-34. doi: 10.1158/0008-5472.CAN-13-3157. Epub 2014 Mar 19.
Therapeutics that target the epidermal growth factor receptor (EGFR) can enhance the cytotoxic effects of ionizing radiation (IR). However, predictive genomic biomarkers of this radiosensitization have remained elusive. By screening 40 non-small cell lung cancer cell (NSCLC) lines, we established a surprising positive correlation between the presence of a KRAS mutation and radiosensitization by the EGFR inhibitors erlotinib and cetuximab. EGFR signaling in KRAS-mutant NSCLC cells promotes chromatin condensation in vitro and in vivo, thereby restricting the number of DNA double-strand breaks (DSB) produced by a given dose of IR. Chromatin condensation in interphase cells is characterized by an unexpected mitosis-like colocalization of serine 10 phosphorylation and lysine 9 trimethylation on histone H3. Aurora B promotes this process in a manner that is codependent upon EGFR and protein kinase C α (PKCα). PKCα, in addition to MEK/ERK signaling, is required for the suppression of DSB-inducible premature senescence by EGFR. Blockade of autophagy results in a mutant KRAS-dependent senescence-to-apoptosis switch in cancer cells treated with IR and erlotinib. In conclusion, we identify EGFR as a molecular target to overcome a novel mechanism of radioresistance in KRAS-mutant tumor cells, which stands in contrast to the unresponsiveness of KRAS-mutant cancers to EGFR-directed agents in monotherapy. Our findings may reposition EGFR-targeted agents for combination with DSB-inducing therapies in KRAS-mutant NSCLC.
靶向表皮生长因子受体 (EGFR) 的治疗方法可以增强电离辐射 (IR) 的细胞毒性作用。然而，这种放射增敏作用的预测性基因组生物标志物仍然难以捉摸。通过筛选 40 种非小细胞肺癌细胞 (NSCLC) 系，我们发现 EGFR 抑制剂厄洛替尼和西妥昔单抗的存在与 KRAS 突变体的放射增敏作用之间存在惊人的正相关。KRAS 突变型 NSCLC 细胞中的 EGFR 信号转导促进体外和体内染色质浓缩，从而限制了给定剂量 IR 产生的 DNA 双链断裂 (DSB) 的数量。有丝分裂期细胞中的染色质浓缩的特点是丝氨酸 10 磷酸化和组蛋白 H3 赖氨酸 9 三甲基化的出乎意料的有丝分裂样共定位。Aurora B 以 EGFR 和蛋白激酶 C α (PKCα) 依赖性的方式促进该过程。PKCα，除了 MEK/ERK 信号转导，还需要 EGFR 抑制 DSB 诱导的过早衰老。自噬的阻断导致在用 IR 和厄洛替尼处理的癌细胞中发生突变型 KRAS 依赖性衰老到凋亡的转换。总之，我们确定 EGFR 是克服 KRAS 突变型肿瘤细胞中新型放射抵抗机制的分子靶标，这与 KRAS 突变型癌症对单药治疗中 EGFR 靶向药物的无反应性形成对比。我们的发现可能重新定位 EGFR 靶向药物，以与 DSB 诱导的治疗方法联合用于 KRAS 突变型 NSCLC。
