Yu Chune, Zhang Min, Song Jinen, Zheng Xiaobo, Xu Guangchao, Bao Yu, Lan Jiang, Luo Dan, Hu Jianping, Li Jingyi Jessica, Shi Hubing
Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 17, 3rd Section, Renmin South Road, Chengdu, 610041, Sichuan, China.
Department of Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China.
Mol Biomed. 2020 Nov 10;1(1):12. doi: 10.1186/s43556-020-00013-0.
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.
PI3K/AKT通路的激活是BRAF靶向治疗最常见的耐药机制之一，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前景的治疗方案之一。尽管在临床前实验和早期临床试验中观察到了强效的药物疗效，但不可避免地出现了双重耐药性。在本研究中，我们系统地探索了黑色素瘤对MAPK抑制剂和PI3K/mTOR抑制剂双重耐药的机制。通过对双重耐药模型的转录组分析，我们发现药物耐受性是由细胞外基质整合素α3β1和α11β1信号介导的。整合素与细胞外基质结合后，激活下游激酶Src，而非FAK、WNT或TGFβ。敲低整合素α3、α11和β1可显著抑制双重耐药亚系的增殖，而对亲本细胞影响不大。尽管抑制Src可抑制AKT、c-JUN和p38的磷酸化，但靶向这些激酶的抑制剂均未逆转模型细胞中的双重耐药性。值得注意的是，Src抑制剂促进了LATS1和YAP1的磷酸化，随后使YAP1从细胞核重新定位到细胞质，促进其进一步降解。靶向YAP1或Src的小分子抑制剂和短发夹RNA均克服了MAPK抑制剂和PI3K/mTOR抑制剂的双重耐药性。总之，我们的数据不仅阐明了整合素-Src-YAP1通路介导的MAPK抑制剂和PI3K/mTOR抑制剂双重耐药机制，还为药物复发的黑色素瘤患者提供了一种潜在的联合治疗方案。
