Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer

Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.

中期因子（Midkine, MDK）是一种肝素结合生长因子，在包括肺癌在内的多种恶性肿瘤中呈高表达。MDK可激活磷脂酰肌醇3-激酶（PI3K）通路并诱导抗凋亡活性，进而增强肿瘤细胞的存活能力。因此，抑制MDK被视为癌症治疗的潜在策略。本研究中，我们报道了一种靶向MDK的新型小分子化合物（iMDK）。iMDK可抑制MDK阳性且携带致癌KRAS突变的H441肺腺癌细胞，以及H520肺鳞癌细胞的增殖，这两类均为目前难以治疗的肺癌类型。但iMDK并不会降低MDK阴性的A549肺腺癌细胞或正常人肺成纤维细胞（NHLF）的细胞活力，这体现了其作用特异性。iMDK可抑制MDK的内源性表达，但对多效生长因子（PTN）、血管内皮生长因子（VEGF）等其他生长因子的表达无显著影响。iMDK通过抑制PI3K通路并诱导细胞凋亡，从而抑制H441细胞的增殖。在体内异种移植瘤小鼠模型中，全身给药iMDK可显著抑制肿瘤生长。利用iMDK抑制MDK，为MDK驱动型肺癌的治疗提供了潜在的新策略。