McFall Thomas, Stites Edward Cooper
Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Mol Cell Oncol. 2020 Jan 15;7(2):1701914. doi: 10.1080/23723556.2019.1701914. eCollection 2020.
Previous analysis of Phase 3 clinical trial data for colorectal cancer patients treated with cetuximab revealed that patients harboring a KRAS mutation did not benefit from treatment. This finding set the stage for one of the first examples of cancer personalized medicine. Confusingly, patients with a Glycine to Aspartic Acid mutation at amino acid 13 of KRAS (KRAS) appeared to respond positively to cetuximab, suggesting this mutation is an exception to the rule that KRAS mutations confer resistance to Epidermal Growth Factor Receptor (EGFR) inhibitors. Oncologists have stated that the mechanism that explains why the KRAS mutation is an exception should be identified before KRAS colorectal cancer patients should be treated differently. We have recently elucidated this mechanism using mathematical modeling of the KRAS biochemical system coupled with experimental biology. The mechanism we revealed involves a cetuximab-mediated reduction in HRAS and NRAS signaling within KRAS cancer cells, owing to impaired binding of KRAS to the tumor suppressor, Neurofibromin (NF1).
先前对接受西妥昔单抗治疗的结直肠癌患者的3期临床试验数据进行的分析表明，携带KRAS突变的患者无法从治疗中获益。这一发现为癌症个性化医疗的首批实例之一奠定了基础。令人困惑的是，KRAS基因第13位氨基酸由甘氨酸突变为天冬氨酸的患者似乎对西妥昔单抗有积极反应，这表明该突变是KRAS突变赋予对表皮生长因子受体（EGFR）抑制剂耐药性这一规则的例外情况。肿瘤学家表示，在对KRAS结直肠癌患者进行不同治疗之前，应先确定解释KRAS突变为何为例外情况的机制。我们最近通过对KRAS生化系统进行数学建模并结合实验生物学阐明了这一机制。我们揭示的机制涉及西妥昔单抗介导的KRAS癌细胞内HRAS和NRAS信号传导减少，这是由于KRAS与肿瘤抑制因子神经纤维瘤蛋白（NF1）的结合受损所致。
