Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo.
Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo.
复制标题
DOI：
10.1073/pnas.2201073119
复制
发表时间：
2022-08-09
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
过度表达致瘤性酪氨酸激酶受体HER2的乳腺癌可以用靶向HER2的抗体（如曲妥珠单抗）或小分子激酶抑制剂（如拉帕替尼）治疗。然而，大多数转移性HER2+乳腺癌患者具有内在耐药性，并且几乎所有患者最终都对HER2靶向治疗产生耐药性。对her2靶向药物的耐药性通常涉及与不同信号通路组成性激活相关的转录重编程。我们发现，抑制CDK8/19中介激酶（一种转录重编程的调节剂）可使HER2+乳腺癌对靶向HER2的药物增敏，从而克服和预防体外和体内的耐药。这些结果表明，HER2和靶向cdk8 /19的药物联合使用可以极大地改善转移性HER2+乳腺癌的治疗效果。过度表达致瘤性酪氨酸激酶受体HER2的乳腺癌（BrCas）可以用HER2靶向抗体（如曲妥珠单抗）或小分子激酶抑制剂（如拉帕替尼）治疗。然而，大多数转移性HER2+ BrCa患者具有内在耐药性，并且几乎所有患者最终都对HER2靶向治疗产生耐药性。对her2靶向药物的耐药性通常涉及与不同信号通路组成性激活相关的转录重编程。我们研究了CDK8/19中介激酶（一种转录重编程调节剂）在HER2+ BrCa对HER2靶向药物的反应中的作用。在接受治疗的HER2+ BrCa患者中，CDK8与较短无复发生存期的相关性在所有基因中排名前1%。选择性CDK8/19抑制剂（senexin B和SNX631）在一组HER2+ BrCa细胞系中显示出与拉帕替尼和曲妥珠单抗的协同相互作用，克服和防止对HER2靶向药物的耐药。协同作用部分通过PI3K/AKT/mTOR途径介导，并通过抑制PI3K而降低。HER2-和cdk8 /19靶向药物联合抑制STAT1和STAT3在S727位点的磷酸化，上调肿瘤抑制因子BTG2。SNX631可部分抑制拉帕替尼敏感或耐药的HER2+乳腺癌细胞形成的异种移植物肿瘤的生长，而SNX631与拉帕替尼联用可强烈抑制肿瘤生长，克服了拉帕替尼耐药。这些影响与肿瘤细胞增殖的减少和异种移植物肿瘤基质成分募集的改变有关。这些结果提示HER2-和cdk8 /19靶向药物联合治疗转移性HER2+ BrCa的潜在临床益处。
Breast cancers that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ breast cancer have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have found that inhibition of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, sensitizes HER2+ breast cancers to HER2-targeting drugs, overcoming and preventing drug resistance, both in vitro and in vivo. These results suggest that combining HER2 and CDK8/19-targeting drugs could greatly improve the treatment outcome in metastatic HER2+ breast cancer. Breast cancers (BrCas) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. CDK8 was in the top 1% of all genes ranked by correlation with shorter relapse-free survival among treated HER2+ BrCa patients. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2+ BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. The synergistic effects were mediated in part through the PI3K/AKT/mTOR pathway and reduced by PI3K inhibition. Combination of HER2- and CDK8/19-targeting agents inhibited STAT1 and STAT3 phosphorylation at S727 and up-regulated tumor suppressor BTG2. The growth of xenograft tumors formed by lapatinib-sensitive or -resistant HER2+ breast cancer cells was partially inhibited by SNX631 alone and strongly suppressed by the combination of SNX631 and lapatinib, overcoming lapatinib resistance. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2+ BrCa.
登录
查看更多内容
影响因子：
7.7
作者：
Clarke, Paul A.;Ortiz-Ruiz, Maria-Jesus;Wienke, Dirk
通讯作者：
Wienke, Dirk
影响因子：
--
作者：
Du, Juan;Wang, LiNa;Zhang, ZongFeng
通讯作者：
Zhang, ZongFeng
影响因子：
6.4
作者：
Banerjee K;Resat H
通讯作者：
Resat H
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J
影响因子：
11.2
作者：
Adler, Adam S.;McCleland, Mark L.;Firestein, Ron
通讯作者：
Firestein, Ron