Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
Department of Biological Sciences, Ajou University, Suwon, Republic of Korea.
Cancer Lett. 2019 Dec 1;466:23-34. doi: 10.1016/j.canlet.2019.09.005. Epub 2019 Sep 12.
The therapeutic targeting of oncogenic KRAS mutant-harboring (KRAS) non-small cell lung cancer (NSCLC) is an urgent unmet need in cancer therapy. Although NSCLC is often driven by epidermal growth factor receptor (EGFR) overexpression and/or mutations, no EGFR-targeted therapy is clinically available for KRAS NSCLC. In this study, we show that integrin β3 expression is associated with the intrinsic resistance of KRAS NSCLCs to the anti-EGFR antibody cetuximab. Further analyses identified an integrin β3-mediated ternary complex comprising NRP1-integrin β3-KRAS and its downstream signaling of PI3K-Akt and RalB-TBK1 as a primary resistance mechanism of KRAS NSCLC to cetuximab treatment. Importantly, we demonstrate that the EGFR/NRP1 dual-targeting bispecific antibody, Ctx-TPP11, attenuates the downstream signaling driven by the ternary complex via the cellular co-internalization and degradation of the NRP1-coupled complex, resulting in the alleviation of cetuximab resistance in KRAS NSCLCs in vitro and in vivo, including patient-derived xenograft mouse models. Our study shows that the dual-targeting of EGFR and NRP1 with a bispecific antibody might be an effective therapeutic strategy for KRAS NSCLC.
针对致癌性 KRAS 突变体（KRAS）非小细胞肺癌（NSCLC）的治疗靶向是癌症治疗中一个迫切未满足的需求。尽管 NSCLC 通常由表皮生长因子受体（EGFR）过表达和/或突变驱动，但目前尚无针对 KRAS NSCLC 的 EGFR 靶向治疗方法。在这项研究中，我们表明整合素β3 的表达与 KRAS NSCLC 对抗 EGFR 抗体西妥昔单抗的内在耐药性有关。进一步的分析确定了一种整合素β3 介导的三元复合物，包括 NRP1-整合素β3-KRAS 及其下游 PI3K-Akt 和 RalB-TBK1 信号通路，作为 KRAS NSCLC 对西妥昔单抗治疗产生原发性耐药的主要机制。重要的是，我们证明了 EGFR/NRP1 双靶标双特异性抗体 Ctx-TPP11 通过细胞共内化和降解 NRP1 偶联复合物，减弱了三元复合物驱动的下游信号，从而缓解了体外和体内的西妥昔单抗耐药性，包括患者来源的异种移植小鼠模型。我们的研究表明，用双特异性抗体双重靶向 EGFR 和 NRP1 可能是治疗 KRAS NSCLC 的一种有效治疗策略。
