{"doi":"10.3389/fcell.2020.00652","title":"Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer","abstract":"With increasing link of integrin/FAK-dependent signaling to NSCLC malignancy, we investigated therapeutic potential of targeting this adhesion receptor-mediated pathway. Our analysis of the TCGA cohort showed that a subset of pro-tumorigenic integrins, including α1β1, α2β1, α3β1, α5β1and α6β4, were frequently amplified or upregulated at genomic or mRNA level in KRAS or EGFR mutation/overexpression-enriched adenocarcinomas. These alterations appeared complimentary and correlated with poor patient survival, regardless of KRAS mutation-coupled αv integrins (p <0.0072). Since the integrin/FAK-dependent signaling is tightly coupled with normal human physiology, we sought for a synthetic lethal-type targeting with VS-6063, a chemical inhibitor of integrin-mediated FAK activity, and A549 cells, which carry 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 a synergy with VS-6063 in terms of 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. Intriguingly, low doses of JQ1 (≤ 0.5µM) markedly escalated efficacy of VS-6063 across a panel of 10 NSCLC cell lines. This catalyst-like effect was in line with our pathway analysis of the TCGA cohort, where c-Myc falls downstream of 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 cellcell adhesion and extracellular matrix (ECM)-dependent cell spreading, reminiscent of phenotypic changes caused by malfunctional E-cadherin or integrins. Paradoxically, this phenotypic impact also coincided with downregulation of EMT-inducting transcription factor ZEB1 and Snail. Moreover, effect of the VS-6063/JQ1 combination was nearly equivalent to that of VS-6063 plus Carboplatin or Osimertinib in terms of cell apoptosis, DNA damage response, and suppression of c-Myc. Taken together, our results suggest that the integrin/FAK and BRD4/c-Myc axes cooperatively drive NSCLC virulence, and a cotargeting may serve as a new line of therapy capable of overcoming EGFR-or RAS/MEK/Erk1/2-driven malignancy.","journal":"Frontiers in Cell and Developmental Biology","year":2020,"id":55683,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":241857,"name":"Kai Cheng","orcid":"0000-0002-6045-0244","position":1,"is_corresponding":false},{"id":290277,"name":"Bingwei Xu","orcid":null,"position":2,"is_corresponding":false},{"id":288496,"name":"Junfeng Shi","orcid":"0000-0001-6424-3149","position":3,"is_corresponding":false},{"id":288497,"name":"Jun Qiang","orcid":"0000-0003-4718-6618","position":4,"is_corresponding":false},{"id":290278,"name":"Shujin Shi","orcid":null,"position":5,"is_corresponding":false},{"id":290279,"name":"Yuanqin Yi","orcid":null,"position":6,"is_corresponding":false},{"id":288498,"name":"Hongxia Li","orcid":"0000-0002-1440-1345","position":7,"is_corresponding":false},{"id":288499,"name":"Tengchuan Jin","orcid":"0000-0002-1395-188X","position":8,"is_corresponding":false},{"id":288500,"name":"Ruihua Guo","orcid":"0000-0001-8414-886X","position":9,"is_corresponding":false},{"id":288501,"name":"Yadi Wu","orcid":"0000-0001-8204-1962","position":10,"is_corresponding":false},{"id":36649,"name":"Zeyi Liu","orcid":"0000-0003-2528-6909","position":11,"is_corresponding":false},{"id":288502,"name":"Xiaowei Wei","orcid":"0000-0002-3802-7845","position":12,"is_corresponding":false},{"id":288503,"name":"Jian‐An Huang","orcid":"0000-0002-0528-2970","position":13,"is_corresponding":false},{"id":288504,"name":"Xiuwei H. Yang","orcid":"0000-0002-5591-6951","position":14,"is_corresponding":false},{"id":288495,"name":"Yang Zhang","orcid":"0000-0002-4061-4408","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T21:05:29.672878Z","pmid":"32793596","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}