抑癌基因DAB2IP之新功能：通过介导“旁路血管生长信号”调控肾癌对靶向药物的敏感性

The development of molecular targeted therapies, which inhibit the VEGFR/PDGFR angiogensis signaling, represents the successful application of translational research in renal cell carcinoma (RCC), and make significant improvements over conventional immunocytokine by bringing clinical benefits for RCC. Unfortunately, less than 40% of RCC patients show response to these agents and nearly all patients will eventually develop resistance. Presently, little is known about how resistance develops, the compresensive understanding of the mechanisms of RCC resistant to targeted therapies is greatly desirable and encouraging. We previously compresensively studied the biological functions of the tumor suppressor DAB2IP, and found it was lost in RCC due to hypermethylation, thus promoting RCC pathogenesis. More importantly, we found the expression of DAB2IP was associated with the drug response of RCC to clinical targeted therapies. Our recently preliminary data indicate that many noncanonical angiogenic growth factors (e.g. FGF2, IL-11) is upregulated in DAB2IP-negative RCC cells. However, it is not clear whether DAB2IP regulates the drug sensitivity of RCC cells to targeted therapies via modulating these alternative angiogenesis pathways. Thus, the present study is firstly aimed to clarify the assocaition of DAB2IP and drug response in RCC and its mechanisms of action by using in vitro and in vivo models. Secondly, biosynthetic peptid mimicing the critical domains of DAB2IP protein will be employed to invesitigate its therapeutic effect for drug-resistant RCC. These will help to understand how drug resistance develops in RCC and provide potential therapeutic strategy for combating RCC.

基于VEGFR/PDGFR血管生长信号的分子靶向药是晚期肾癌治疗史上的巨大进步，但其疗效昙花一现，耐药目前成为影响患者获益的最大障碍，明确肾癌血管靶向药耐药的分子机制并寻找全新的作用靶点迫在眉睫。我们前期在系统研究抑癌基因DAB2IP的生物功能过程中，发现其在肾癌内高度甲基化而表达抑制，进而促进肾癌发生；更为重要的是，我们还发现DAB2IP与患者对临床血管靶向药的反应性密切相关。我们近期预实验提示DAB2IP缺失的肾癌细胞内非经典的促血管生长因子FGF2及IL-11上调，但DAB2IP是否通过介导这些“旁路血管生长途径”来影响靶向药的敏感性不得而知。本项目延续前期研究，拟首先采用体内、外实验阐明DAB2IP在VEGFR/PDGFR靶向药敏感性中的作用及机制；其次探索模拟DAB2IP关键功能结构域的生物多肽对耐药的肾癌细胞的治疗效应，以期明确肾癌对血管靶向药耐药的分子机制并探索新的治疗策略。

基于mTOR/HIF-α/VEGF/VEGFR血管生长信号的分子靶向药是晚期肾癌治疗史上的巨大进步，但其疗效昙花一现，耐药目前成为影响患者获益的最大障碍，明确肾癌血管靶向药耐药的分子机制并寻找全新的作用靶点迫在眉睫。我们前期在系统研究抑癌基因DAB2IP的生物功能过程中，发现其在肾癌内高度甲基化而表达抑制，进而促进肾癌发生；重要的是DAB2IP缺失的肾癌细胞内经典的促血管生长信号mTOR/HIF-α/VEGF/VEGFR活化，促进肾癌生长，但是阻断这条信号通路的靶向药不能完全抑制肿瘤生长，因此我们推测DAB2IP还能介导“旁路血管生长途径”影响靶向药的敏感性。本项目延续前期研究，一方面证实DAB2IP 与患者对临床现用的血管靶向药的反应性密切相关，除了调控上述经典的促血管生长信号外，DAB2IP的缺失还促进了FGF2/FGFR介导的“旁路血管生长途径”的活化，因而，在联合应用靶向VEGFR及FGFR信号的药物能显示出对耐药性肾癌的抑制效应。另一方面，本课题还研究发现了DAB2IP的新功能，即可通过其C-端的CPR结构域来促进p27的磷酸化和细胞浆内的范素化降解。最后，本课题还探索了针对DAB2IP阴性的肾癌细胞（耐药性肾癌）的具体高效抑制作用小分子化合物CYD-6-17，并证实CYD-6-17可特异性靶向耐药性肾癌内分子靶点PDPK1及其下游信号来发挥抑癌效应。总之，本研究解析肾癌对靶向药物耐药的部分机理，并阐明了DAB2IP所调控的肾癌耐药的“旁路血管生长信号”机制，还探索了耐药性肾癌的潜在新靶点和治疗小分子化合物，为临床肾癌治疗提供了新思路和新选择。