Department of Biological Regulation, Rehovot, Israel.
Department of Biological Services, Weizmann Institute of Science, Rehovot, Israel.
Clin Cancer Res. 2018 Nov 15;24(22):5610-5621. doi: 10.1158/1078-0432.CCR-18-0450. Epub 2018 Jul 2.
Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and an alternative therapeutic approach making use of antibodies. An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed. Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3. Our assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance. .
由于第三代 EGFR 酪氨酸激酶抑制剂（TKI）奥希替尼出现耐药性，对于因新突变或旁路机制而失去敏感性的肺癌患者，没有靶向治疗方法。我们在动物和临床试验中检查了一种利用抗体的替代治疗方法。我们使用了一种对奥希替尼敏感的肺癌动物模型，该模型会迅速产生耐药性。为了克服我们之前报道的 ERK 的代偿性过度激活，我们将抗 EGFR 抗体（西妥昔单抗）与其他抗体以及亚治疗剂量的奥希替尼联合使用，并检测了癌细胞凋亡。我们的动物研究确定了三种临床批准药物的联合用药方案，即西妥昔单抗、曲妥珠单抗（一种抗 HER2 mAb）和奥希替尼（低剂量），作为一种有效且持久的治疗方法，能够预防奥希替尼耐药的发生。连续的联合治疗方案足以有效抑制肿瘤并防止复发。培养细胞的研究和肿瘤提取物的分析表明，两种 mAb 和一种亚治疗剂量的 TKI 联合使用可将 EGFR 和 HER2 进行分类降解；协同增强细胞凋亡；抑制 ERK 激活；并减少几种旁路蛋白的丰度，即 MET、AXL 和 HER3。我们的实验和动物研究确定了一种有效的临床批准药物联合方案，可能克服临床环境中对不可逆 TKI 的耐药性。我们提出的结果将该药物联合方案的持久效果归因于同时阻断了几种经过充分研究的耐药机制。
