AXL和易出错的DNA复制带来耐药性，并为egfr突变型肺癌的治疗提供策略

SCI

5 Octember 2022

AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer 

(Cancer Discovery, IF: 38.272)

Noronha A, Belugali Nataraj N, Sang Lee J, et al. AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer. Cancer Discov 2022. DOI: 10.1158/2159-8290.CD-22-0111.

Corresponding Author: Y osef Y arden, Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972-8-934-3974; Fax: 972-8-934-2488; E-mail: yosef.yarden@weizmann.ac.il

ABSTRACT 摘要

Anticancer therapies have been limited by the 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 the 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, whereas 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.

抗癌治疗一直受到突变和其他适应性的限制。在细菌中，抗生素激活SOS反应，调动容易出错的因素，允许以突变形成为代价进行持续复制。我们研究了用EGFR抑制剂(EGFRi)治疗肺癌是否同样会引起超突变。在循环耐药持久性(DTP)细胞和EGFR治疗后残留病灶患者中，我们观察到GAS6的上调，而GAS6的受体AXL的消融消除了耐药性。相反地，AXL过表达增强了DTP的存活，并加速了T790M的出现，T790M是耐药细胞典型的EGFR突变。机制上，AXL诱导低保真度DNA聚合酶，并通过促进类泛素化激活其组织导体RAD18。代谢组学发现了另一种超突变，由AXL驱动的MYC激活，增加了嘌呤合成，并出现嘧啶失衡。将抗AXL联合治疗与DTP向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，肿瘤通过使用药理学上可靶向的内源性突变体来耐受治疗。

SIGNIFICANCE 意义

EGFR-mutant lung cancers treated with kinase inhibitors often evolve resistance due to secondary mutations. We report that in similarity to the bacterial SOS response stimulated by antibiotics, endogenous mutators are activated in drug-treated cells, and this heralds tolerance. Blocking the process prevented resistance in xenograft models, which offers new treatment strategies.

用激酶抑制剂治疗的EGFR突变肺癌往往由于继发性突变而产生耐药性。我们报道了与抗生素刺激的细菌SOS反应相似，内源性突变体在药物治疗的细胞中被激活，这预示着耐药性。阻断该过程可防止异种移植模型的耐药性，这提供了新的治疗策略。