Integrin-Src-YAP1 signaling mediates the melanoma acquired resistance to MAPK and PI3K/mTOR dual targeted therapy.
Integrin-Src-YAP1 signaling mediates the melanoma acquired resistance to MAPK and PI3K/mTOR dual targeted therapy.
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Integrin-Src-YAP1信号介导黑色素瘤对MAPK和PI3K/mTOR双靶向治疗的获得性耐药
DOI：
10.1186/s43556-020-00013-0
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发表时间：
2020-11-10
影响因子：
4
通讯作者：
Shi H
中科院分区：
文献类型：
--
作者：
Yu C;Zhang M;Song J;Zheng X;Xu G;Bao Y;Lan J;Luo D;Hu J;Li JJ;Shi H
PI3K/AKT通路的激活是braf靶向治疗最容易复发的耐药机制之一，MAPK和PI3K/AKT抑制剂联合使用成为braf靶向复发黑色素瘤患者最有希望的治疗方案之一。虽然在临床前实验和早期临床试验中观察到强有力的药物疗效，但不可避免地观察到双药耐药。在这项研究中，我们系统地探讨了黑色素瘤中MAPKi和PI3K/mTORi双药耐药的机制。通过双耐药模型的转录组学解剖，我们发现耐药是由ecm -整合素α3β1和α11β1信号介导的。结合ECM后，整合素激活下游激酶Src，而不是FAK、WNT或TGFβ。敲低整合素α3、α11和β1可显著抑制双药耐药亚群的增殖，而对亲本细胞影响不大。尽管Src抑制抑制了AKT、c-JUN和p38的磷酸化，但没有一种靶向这些激酶的抑制剂逆转了模型细胞的双药耐药。值得注意的是，Src抑制剂促进了LATS1和YAP1的磷酸化，随后将YAP1从细胞核重新定位到细胞质中，促进了进一步的降解。靶向YAP1或Src的小分子抑制剂和shrna都克服了MAPKi和PI3K/mTORi双药耐药。总之，我们的数据不仅阐明了整合素- src - yap1通路介导的MAPKi和PI3K/mTORi双耐药机制，而且为药物复发黑色素瘤患者提供了潜在的联合治疗方案。
Activation of PI3K/AKT pathway is one of the most recurrent resistant mechanisms for BRAF-targeted therapy, and the combination of MAPK and PI3K/AKT inhibitors becomes one of the most promising regimens for BRAF-targeted relapsed melanoma patients. Although the potent drug efficacy was observed in preclinical experiments and early clinical trials, the dual-drug resistance is inevitable observed. In this study, we systematically explored the mechanisms of dual-drug resistance to MAPKi and PI3K/mTORi in melanoma. With transcriptomic dissection of dual-drug resistant models, we identified that the drug tolerance was mediated by ECM-integrins α3β1 and α11β1 signaling. Upon binding ECM, the integrins activated downstream kinase Src rather than FAK, WNT, or TGFβ. Knockdown of integrins α3, α11, and β1 significantly inhibited the proliferation of dual-drug resistant sublines while with trivial effects on parental cells. Although Src inhibition suppressed the phosphorylation of AKT, c-JUN, and p38, none of inhibitors targeting these kinases reversed the dual-drug resistance in model cells. Notably, Src inhibitor promoted the phosphorylations of LATS1 and YAP1, subsequently, re-localized YAP1 from nucleus to cytosol facilitating further degradation. Both small molecule inhibitors and shRNAs targeting YAP1 or Src overcame the MAPKi and PI3K/mTORi dual-drug resistance. In conclusion, our data not only illuminated an integrin-Src-YAP1 pathway mediated MAPKi and PI3K/mTORi dual-drug resistant mechanism but also provided a potential combinatorial regimen for the drug-relapsed melanoma patients.