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upfront 联合使用抗体和 EGFR 抑制剂可预防肺癌模型中的序贯治疗。

Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models.

机构信息

Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.

Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.

出版信息

EMBO Mol Med. 2021 Apr 9;13(4):e13144. doi: 10.15252/emmm.202013144. Epub 2021 Mar 4.

DOI:10.15252/emmm.202013144
PMID:33660397
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8033519/
Abstract

Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti-cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first-, second-, and third-generation drugs. To explore alternatives to such whack-a-mole strategies, we simulated in patient-derived xenograft models the situation of patients receiving first-line TKIs. Monotherapies comprising approved first-line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug-drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance-conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next-generation TKIs.

摘要

一些抗菌疗法需要使用不同的抗生素进行序贯治疗，但这种方法是否对抗癌酪氨酸激酶抑制剂 (TKI) 最有效仍存在争议。EGFR 突变可识别可从 TKI 中获益的肺癌患者，但大多数患者会对第一代、第二代和第三代药物产生耐药性。为了探索替代这种打地鼠策略的方法，我们在患者来源的异种移植模型中模拟了接受一线 TKI 治疗的患者的情况。比较了包含已批准的一线 TKI 的单药治疗与针对 EGFR 和 HER2 的抗体联合治疗。我们观察到所有药物组合相对于各自的单药治疗均具有均匀且强大的优势。延长治疗时间、高 TKI 剂量和药物特异性对于药物相互作用至关重要。阻断有丝分裂所必需的途径（例如，FOXM1），以及下调耐药相关受体（例如，AXL），可能是药物相互作用的基础。因此，使用 TKI 和抗体联合的一线治疗可以预防耐药性的出现，从而可能取代广泛应用的下一代 TKI 序贯治疗。

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