Department of Neurosurgery, Brain Tumor Center Amsterdam, Amsterdam University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HZ, Amsterdam, the Netherlands.
Department of Neurosurgery, Brain Tumor Center Amsterdam, Amsterdam University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HZ, Amsterdam, the Netherlands; Division of Biology, Nature Science Building, 9500 Gilman Drive, CA, 92093-0377, United States.
Drug Resist Updat. 2019 Mar;43:29-37. doi: 10.1016/j.drup.2019.04.002. Epub 2019 Apr 22.
Targeted therapy against driver mutations responsible for cancer progression has been shown to be effective in many tumor types. For glioblastoma (GBM), the epidermal growth factor receptor (EGFR) gene is the most frequently mutated oncogenic driver and has therefore been considered an attractive target for therapy. However, so far responses to EGFR-pathway inhibitors have been disappointing. We performed an exhaustive analysis of the mechanisms that might account for therapy resistance against EGFR inhibition. We define two major mechanisms of resistance and propose modalities to overcome them. The first resistance mechanism concerns target independence. In this case, cells have lost expression of the EGFR protein and experience no negative impact of EGFR targeting. Loss of extrachromosomally encoded EGFR as present in double minute DNA is a frequent mechanism for this type of drug resistance. The second mechanism concerns target compensation. In this case, cells will counteract EGFR inhibition by activation of compensatory pathways that render them independent of EGFR signaling. Compensatory pathway candidates are platelet-derived growth factor β (PDGFβ), Insulin-like growth factor 1 (IGFR1) and cMET and their downstream targets, all not commonly mutated at the time of diagnosis alongside EGFR mutation. Given that both mechanisms make cells independent of EGFR expression, other means have to be found to eradicate drug resistant cells. To this end we suggest rational strategies which include the use of multi-target therapies that hit truncation mutations (mechanism 1) or multi-target therapies to co-inhibit compensatory proteins (mechanism 2).
针对导致癌症进展的驱动突变的靶向治疗已被证明在许多肿瘤类型中有效。对于胶质母细胞瘤（GBM），表皮生长因子受体（EGFR）基因是最常发生突变的致癌驱动基因，因此被认为是治疗的一个有吸引力的靶点。然而，到目前为止，针对 EGFR 通路抑制剂的反应一直令人失望。我们对可能导致 EGFR 抑制治疗耐药的机制进行了全面分析。我们定义了两种主要的耐药机制，并提出了克服这些机制的方法。第一种耐药机制涉及靶标独立性。在这种情况下，细胞已经失去了 EGFR 蛋白的表达，并且不受 EGFR 靶向的负面影响。双微体 DNA 中存在的额外染色体编码的 EGFR 的丢失是这种类型药物耐药的常见机制。第二种机制涉及靶标补偿。在这种情况下，细胞将通过激活补偿途径来对抗 EGFR 抑制，从而使它们独立于 EGFR 信号。补偿途径候选物是血小板衍生生长因子β（PDGFβ）、胰岛素样生长因子 1（IGF1）和 cMET 及其下游靶标，这些靶标在 EGFR 突变时通常不会与 EGFR 突变同时发生突变。鉴于这两种机制使细胞独立于 EGFR 表达，必须找到其他方法来消灭耐药细胞。为此，我们建议采用合理的策略，包括使用针对截断突变的多靶治疗（机制 1）或多靶治疗来共同抑制补偿蛋白（机制 2）。
