Shen Tianli, Chen Zhengxi, Qiao Ju, Sun Xuejun, Xiao Qian
1Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi China.
2Department of Pharmacology, School of Medicine, Yale University, 10 Amistad St, New Haven, CT USA.
Cell Death Discov. 2019 Jul 31;5:123. doi: 10.1038/s41420-019-0204-4. eCollection 2019.
Adenomatous polyposis coli () and proto-oncogene () mutations frequently co-occur in non-small cell lung cancer. Inactivating mutations in colorectal carcinoma has been well characterized, leading to the approaches targeting on dysregulated pathway. However, it remains undetermined whether such approaches are also applicable to non-small cell lung cancer patients harboring similar mutations of . Dickkopf-related protein 2 (DKK2) is a Wnt antagonist. Our previous study has proved that anti-DKK2 antibody 5F8 suppressed the growth of colorectal carcinoma with mutations, illustrating a new target agent of APC-mutated tumors. This study aimed to investigate the potential of applying anti-DKK2 antibody to non-small cell lung cancer with mutations. We found significant upregulation of Dkk2 expression in -mutated lung cancers. Administration of DKK2 antibody inhibited cancer growth modulating tumor immune microenvironment in lung cancer mouse models. Our study provided strong evidence supporting mutations-directed applications of anti-DKK2 targeted therapy in a wide range of cancer types, including lung cancer.
腺瘤性结肠息肉病（APC）和原癌基因（KRAS）突变在非小细胞肺癌中经常共同出现。结直肠癌中APC失活突变已得到充分表征，从而产生了针对失调的Wnt通路的治疗方法。然而，这些方法是否也适用于携带类似APC突变的非小细胞肺癌患者仍未确定。Dickkopf相关蛋白2（DKK2）是一种Wnt拮抗剂。我们之前的研究证明，抗DKK2抗体5F8抑制了携带KRAS突变的结直肠癌的生长，说明了APC突变肿瘤的一种新的靶向药物。本研究旨在探讨将抗DKK2抗体应用于携带KRAS突变的非小细胞肺癌的潜力。我们发现在KRAS突变的肺癌中Dkk2表达显著上调。在肺癌小鼠模型中，给予DKK2抗体通过调节肿瘤免疫微环境抑制了癌症生长。我们的研究提供了强有力的证据，支持针对KRAS突变的抗DKK2靶向治疗在包括肺癌在内的广泛癌症类型中的应用。
