Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
Sci Transl Med. 2018 Jun 20;10(446). doi: 10.1126/scitranslmed.aao2565.
KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRAS-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.
KRAS 是人类肺腺癌中最常发生突变的驱动致癌基因。目前尚无针对 KRAS 驱动型肺癌的临床验证治疗策略。KRAS 中的激活突变被认为赋予了其对上游信号的独立性；然而，最近的数据表明，这种独立性可能并非绝对。我们发现，KRAS 驱动的肺肿瘤的发生和进展需要 ERBB 家族受体酪氨酸激酶（RTKs）的输入：在 KRAS 驱动的肺肿瘤发展的最早阶段就表达和激活了多种 ERBB RTKs，并且用多 ERBB 抑制剂治疗可抑制 KRAS 驱动的肺肿瘤的形成。我们提供的证据表明，ERBB 活性可放大核心 RAS 通路的信号，从而支持 KRAS 突变肿瘤细胞在培养中的增殖，并在体内进展为侵袭性疾病。ERBB 网络的短暂药理抑制可增强 MEK（丝裂原活化蛋白激酶激酶）抑制在同源肿瘤环境中的治疗效果。我们的数据表明，具有 KRAS 驱动性疾病的肺癌患者可能受益于在合理设计的治疗策略中加入多 ERBB 抑制剂。
