AXL和易错DNA复制提供了耐药性，并提供了治疗EGFR突变肺癌的策略

Abstract 摘要

Anti-cancer therapies have been limited by emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error‐prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease we observed upregulation of GAS6, while ablation of GAS6’s receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators.

抗癌疗法一直受到突变和其他基因改变的限制。在细菌中，抗生素激活了SOS反应，这调动了易错因素，以突变为代价允许连续复制。我们研究了使用EGFR抑制剂(EGFRi)治疗肺癌是否同样涉及高突变体。在循环持续耐药 (DTP)细胞和EGFR治疗后出现残留疾病的患者中，我们观察到GAS6上调，而 GAS6 受体 AXL 的消除消除了耐药性。相反，AXL过表达提高了DTP的存活率，并加速了EGFR耐药细胞的典型突变T790M的出现。从机制上讲，AXL诱导低保真DNA聚合酶，并通过促进类泛素化作用激活其组织者RAD18。代谢组学发现了另一种高突变因子，AXL驱动的MYC激活和嘧啶不平衡的嘌呤合成增加。将抗AXL联合治疗与从DTP到耐药细胞的转变相结合，治愈了患者来源的异种移植。因此，与细菌类似，肿瘤通过药物靶向性内源性突变体耐受治疗。