PO.PR02.01 · 预防研究
用于评估靶向 EGFR L858R/T790M 和 EGFR L858R/T790M/C979S 耐药突变的疗法的新型同基因 NSCLC 模型
Novel syngeneic models for evaluating therapies targeting EGFR L858R/T790M and EGFR L858R/T790M/C979S resistance mutations in NSCLC
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
第一代和第二代 EGFR-TKI 药物均显著改善了携带 EGFR 激活突变的 NSCLC 患者的生存。然而，继发性 T790M 突变会迅速驱动对这些药物的耐药。第三代 EGFR-TKI 可有效抑制 T790M 突变体，但随后的 C797S 突变会消除其共价结合，从而使目前没有已获批的靶向治疗选择。因此，我们实验室构建了携带人 EGFR L858R/T790M 或 EGFR L858R/T790M/C979S 的条件性敲入 C57BL/6 小鼠，这些小鼠可快速自发形成 NSCLC 并产生原代肿瘤细胞系。在同基因、免疫健全的 C57BL/6 宿主中，研究中的第四代 TKI BLU-945 显著抑制了 EGFR L858R/T790M 和 EGFR L858R/T790M/C979S 两种肿瘤的生长。相比之下，奥希替尼仅对 EGFR L858R/T790M 有效，而对 EGFR L858R/T790M/C979S 突变无效。这表明我们的新型小鼠模型忠实地重现并能够在体内逆转奥希替尼耐药。
查看英文原文 English abstract
Both the first and second-generation EGFR-TKIs drugs have markedly improved the survival of NSCLC patients with activating EGFR mutations. However a secondary T790M mutation rapidly drives resistance towards these drugs. Third-generation EGFR-TKIs potently suppress the T790M mutant, but the subsequent C797S mutation abolishes their covalent binding, leaving no currently approved targeted options. Therefore, our laboratory generated conditional knock-in C57BL/6 mice harboring human EGFR L858R/T790M or EGFR L858R/T790M/C979S , which quickly develop spontaneous NSCLC and yield primary tumor cell lines.In syngeneic, immune-competent C57BL/6 hosts, the fourth-generation TKI under research, BLU-945, markedly inhibited both EGFR L858R/T790M and EGFR L858R/T790M/C979S tumor growth. In contrast, osimertinib was effective only against EGFR L858R/T790M , but failing against the EGFR L858R/T790M/C979S mutation. This demonstrates how our novel mouse models faithfully recapitulate and allow the reversal of osimertinib resistance in vivo .
利益披露 Disclosure
L. Ci,
Shanghai Model Organisms Center, Inc. Other, Parent Company.
K. Zhou,
Shanghai Model Organisms Center, Inc. Other, Parent Company.
J. Liu,
Shanghai Model Organisms Center, Inc. Other, Parent Company.
R. Sun,
Shanghai Model Organisms Center, Inc. Other, Parent Company.