文献类型： 外文期刊

作者： Zhang, Yang ¹ ; Cheng, Kai ⁴ ; Xu, Bingwei ² ; Shi, Junfeng ⁵ ; Qiang, Jun ⁶ ; Shi, Shujin ⁵ ; Yi, Yuanqin ² ; Li, Hongxi ¹ ;

作者机构： 1.Soochow Univ, Affiliated Hosp 1, Dept Resp Med, Suzhou, Peoples R China

2.Univ Kentucky, Dept Pharmacol & Nutr Sci, Lexington, KY 40506 USA

3.Univ Kentucky, Markey Canc Ctr, Lexington, KY 40506 USA

4.Nanjing Univ, Nanjing Jinling Hosp, Sch Med, Dept Pathol, Nanjing, Peoples R China

5.Nanjing Med Univ, Dept Oncol, Nanjing, Peoples R China

6.Chinese Acad Fishery Sci, Freshwater Fisheries Res Ctr, Minist Agr, Wuxi, Jiangsu, Peoples R China

7.Nanjing Agr Univ, Fisheries Coll, Wuxi, Jiangsu, Peoples R China

8.China Med Univ, Affiliated Hosp 1, Canc Inst, Shenyang, Peoples R China

9.Univ Sci & Technol China, Div Life Sci & Med, Lab Struct Immunol, Hefei, Peoples R China

10.Shanghai Ocean Univ, Coll Food Sci & Technol, Shanghai, Peoples R China

关键词： lung cancer; FAK; BRD4; integrins; KRAS targeted therapy

期刊名称：FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY （ 影响因子：6.684； 五年影响因子：7.219 ）

ISSN： 2296-634X

年卷期： 2020 年 8 卷

页码：

收录情况： SCI

摘要： We investigated the therapeutic potential of targeting integrin/FAK-dependent signaling, an adhesion receptor-mediated pathway that has been increasingly linked to non-small cell lung cancer (NSCLC) malignancy. Our analysis of the TCGA cohort showed that a subset of pro-tumorigenic integrins, including alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, and alpha 6 beta 4, were frequently amplified or upregulated at the genomic or mRNA level in KRAS or EGFR mutation/overexpression-enriched adenocarcinomas. These alterations appeared complementary, correlated with poor patient survival (p< 0.0072), and were collaborative with KRAS mutation-coupled alpha v integrins (p< 0.00159). Since integrin/FAK-dependent signaling is tightly coupled with normal human physiology, we sought to use a synthetic lethal-type targeting comprising of VS-6063, a chemical inhibitor of integrin-mediated FAK activity, and A549 cells, which carry a KRAS mutation and EGFR overexpression. Our screening analysis revealed that JQ1 and IBET-762, inhibitors of epigenetic reader BRD4, and LBH589, a pan inhibitor of histone deacetylases (HDACs), exhibited synergy with VS-6063 in mitigating tumor cell viability. This epigenetic link was corroborated by strong effects of additional inhibitors and RNAi-mediated knockdown of FAK and BRD4 or its downstream effector, c-Myc. Low doses of JQ1 (<= 0.5 mu M) markedly escalated efficacy of VS-6063 across a panel of 10 NSCLC cell lines. This catalyst-like effect is in line with the oncogenic landscape in the TCGA cohort since c-Myc falls downstream of the KRAS and EGFR oncogenes. Mechanistically, co-inhibiting the integrin-FAK and BRD4/c-Myc axes synergistically induced apoptotic cell death and DNA damage response, and impaired stemness-associated tumorsphere formation. These effects were accompanied by a marked inhibition of Akt- and p130Cas/Src-dependent signaling, but not Erk1/2 activity. Meanwhile, JQ1 alone or in combination with VS-6063 attenuated cell-cell adhesion and extracellular matrix (ECM)-dependent cell spreading, which is reminiscent of phenotype induced by malfunctional E-cadherin or integrins. Paradoxically, this phenotypic impact coincided with downregulation of epithelial-mesenchymal transition (EMT)-inducting transcription factor ZEB1 or Snail. Finally, we showed that the effect of the VS-6063/JQ1 combination was nearly equivalent to that of VS-6063 plus Carboplatin or Osimertinib. Overall, our study indicates that the integrin/FAK and BRD4/c-Myc axes cooperatively drive NSCLC virulence, and a co-targeting may provide a line of therapy capable of overcoming EGFR/KRAS-driven malignancy.