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基因突变的靶向治疗已被证明在许多类型的肿瘤中都是有效的。对于胶质母细胞瘤（GBM），表皮生长因子受体（EGFR）基因是最常见的突变致癌驱动子，因此被认为是治疗的诱人靶标。然而，到目前为止，对EGFR途径抑制剂的反应令人失望。我们对可能解释针对EGFR抑制的治疗耐药性的机制进行了详尽的分析。我们定义了两种主要的抵抗机制，并提出了克服它们的方式。第一个抵抗机制涉及目标独立性。在这种情况下，细胞已经丧失了EGFR蛋白的表达，并且没有受到EGFR靶向的负面影响。双重DNA中存在的染色体外编码的EGFR缺失是这种耐药性的常见机制。第二种机制涉及目标补偿。在这种情况下，细胞将通过激活补偿途径来抵消EGFR抑制，使它们独立于EGFR信号传导。代偿途径的候选者是血小板衍生的生长因子β（PDGFβ），胰岛素样生长因子1（IGFR1）和cMET及其下游靶标，它们在诊断时通常不伴随EGFR突变而突变。考虑到这两种机制都使细胞独立于EGFR表达，必须找到其他方法来根除耐药性细胞。