Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer
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, includ...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2020-07-01
|
Series: | Frontiers in Cell and Developmental Biology |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.00652/full |
id |
doaj-a81bd69401dc44c9830497613399ff30 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yang Zhang Yang Zhang Yang Zhang Kai Cheng Bingwei Xu Bingwei Xu Junfeng Shi Jun Qiang Jun Qiang Shujin Shi Yuanqin Yi Yuanqin Yi Yuanqin Yi Hongxia Li Hongxia Li Hongxia Li Hongxia Li Tengchuan Jin Ruihua Guo Yadi Wu Yadi Wu Zeyi Liu Xiaowei Wei Jian-An Huang Xiuwei H. Yang Xiuwei H. Yang |
spellingShingle |
Yang Zhang Yang Zhang Yang Zhang Kai Cheng Bingwei Xu Bingwei Xu Junfeng Shi Jun Qiang Jun Qiang Shujin Shi Yuanqin Yi Yuanqin Yi Yuanqin Yi Hongxia Li Hongxia Li Hongxia Li Hongxia Li Tengchuan Jin Ruihua Guo Yadi Wu Yadi Wu Zeyi Liu Xiaowei Wei Jian-An Huang Xiuwei H. Yang Xiuwei H. Yang Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer Frontiers in Cell and Developmental Biology lung cancer FAK BRD4 integrins KRAS targeted therapy |
author_facet |
Yang Zhang Yang Zhang Yang Zhang Kai Cheng Bingwei Xu Bingwei Xu Junfeng Shi Jun Qiang Jun Qiang Shujin Shi Yuanqin Yi Yuanqin Yi Yuanqin Yi Hongxia Li Hongxia Li Hongxia Li Hongxia Li Tengchuan Jin Ruihua Guo Yadi Wu Yadi Wu Zeyi Liu Xiaowei Wei Jian-An Huang Xiuwei H. Yang Xiuwei H. Yang |
author_sort |
Yang Zhang |
title |
Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer |
title_short |
Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer |
title_full |
Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer |
title_fullStr |
Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer |
title_full_unstemmed |
Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer |
title_sort |
epigenetic input dictates the threshold of targeting of the integrin-dependent pathway in non-small cell lung cancer |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2020-07-01 |
description |
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 α1β1, α2β1, α3β1, α5β1, and α6β4, 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 αv 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 μM) 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. |
topic |
lung cancer FAK BRD4 integrins KRAS targeted therapy |
url |
https://www.frontiersin.org/article/10.3389/fcell.2020.00652/full |
work_keys_str_mv |
AT yangzhang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT yangzhang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT yangzhang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT kaicheng epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT bingweixu epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT bingweixu epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT junfengshi epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT junqiang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT junqiang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT shujinshi epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT yuanqinyi epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT yuanqinyi epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT yuanqinyi epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT hongxiali epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT hongxiali epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT hongxiali epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT hongxiali epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT tengchuanjin epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT ruihuaguo epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT yadiwu epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT yadiwu epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT zeyiliu epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT xiaoweiwei epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT jiananhuang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT xiuweihyang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer AT xiuweihyang epigeneticinputdictatesthethresholdoftargetingoftheintegrindependentpathwayinnonsmallcelllungcancer |
_version_ |
1724523769629769728 |
spelling |
doaj-a81bd69401dc44c9830497613399ff302020-11-25T03:42:45ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-07-01810.3389/fcell.2020.00652560485Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung CancerYang Zhang0Yang Zhang1Yang Zhang2Kai Cheng3Bingwei Xu4Bingwei Xu5Junfeng Shi6Jun Qiang7Jun Qiang8Shujin Shi9Yuanqin Yi10Yuanqin Yi11Yuanqin Yi12Hongxia Li13Hongxia Li14Hongxia Li15Hongxia Li16Tengchuan Jin17Ruihua Guo18Yadi Wu19Yadi Wu20Zeyi Liu21Xiaowei Wei22Jian-An Huang23Xiuwei H. Yang24Xiuwei H. Yang25Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United StatesMarkey Cancer Center, University of Kentucky, Lexington, KY, United StatesDepartment of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, ChinaDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United StatesMarkey Cancer Center, University of Kentucky, Lexington, KY, United StatesDepartment of Oncology, Nanjing Medical University, Nanjing, ChinaMinistry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, ChinaFisheries College, Nanjing Agricultural University, Wuxi, ChinaDepartment of Oncology, Nanjing Medical University, Nanjing, ChinaDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United StatesMarkey Cancer Center, University of Kentucky, Lexington, KY, United StatesCancer Institute, The First Affiliated Hospital of China Medical University, Shenyang, ChinaDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United StatesMarkey Cancer Center, University of Kentucky, Lexington, KY, United StatesMinistry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, ChinaFisheries College, Nanjing Agricultural University, Wuxi, ChinaLaboratory of Structural Immunology, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China0College of Food Science and Technology, Shanghai Ocean University, Shanghai, ChinaDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United StatesMarkey Cancer Center, University of Kentucky, Lexington, KY, United StatesDepartment of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Oncology, Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United StatesMarkey Cancer Center, University of Kentucky, Lexington, KY, United StatesWe 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 α1β1, α2β1, α3β1, α5β1, and α6β4, 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 αv 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 μM) 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.https://www.frontiersin.org/article/10.3389/fcell.2020.00652/fulllung cancerFAKBRD4integrinsKRAS targeted therapy |