平滑蛋白变体解释了基底细胞癌中大部分的耐药性。
Smoothened variants explain the majority of drug resistance in basal cell carcinoma.
作者信息
Atwood Scott X, Sarin Kavita Y, Whitson Ramon J, Li Jiang R, Kim Geurim, Rezaee Melika, Ally Mina S, Kim Jinah, Yao Catherine, Chang Anne Lynn S, Oro Anthony E, Tang Jean Y
机构信息
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
出版信息
Cancer Cell. 2015 Mar 9;27(3):342-53. doi: 10.1016/j.ccell.2015.02.002.
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
晚期基底细胞癌（BCC）常常通过未知机制对 smoothened（SMO）抑制剂产生耐药性。在此，我们在 50%（44 例中的 22 例）耐药性 BCC 中鉴定出 SMO 突变，并表明这些突变在存在 SMO 抑制剂的情况下维持 Hedgehog 信号传导。改变包括四个定义抑制剂结合位点的配体结合口袋突变以及四个赋予组成型活性和抑制剂抗性的变体，揭示了确保受体自抑制的关键残基。在存在 SMO 抑制剂的情况下，含有任何一类 SMO 突变体的肿瘤细胞比含有野生型 SMO 的细胞更具竞争力。最后，我们表明两类 SMO 变体均对在 SMO 下游起作用的 aPKC-ι/λ 或 GLI2 抑制剂有反应，为 GLI 拮抗剂的临床应用奠定了基础。
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