PMID- 35655775 OWN - NLM STAT- MEDLINE DCOM- 20220606 LR - 20220716 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule. PG - 872470 LID - 10.3389/fimmu.2022.872470 [doi] LID - 872470 AB - Lung cancer poses a serious threat to human health and has recently been tagged the most common malignant disease with the highest incidence and mortality rate. Although epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, patients often develop resistance to these drugs. There is therefore a need to identify new drug candidates with multitarget potential for treating NSCLC. We hereby provide preclinical evidence of the therapeutic efficacy of NLOC-015A a multitarget small-molecule inhibitor of EGFR/mitogen-activated protein (MAP) kinase kinase 1 (MAP2K1)/mammalian target of rapamycin (mTOR)/yes-associated protein 1 (YAP1) for the treatment NSCLC. Our multi-omics analysis of clinical data from cohorts of NSCLC revealed that dysregulation of EGFR/MAP2K1/mTOR/YAP1 signaling pathways was associated with the progression, therapeutic resistance, immune-invasive phenotypes, and worse prognoses of NSCLC patients. Analysis of single-cell RNA sequencing datasets revealed that MAP2K1, mTOR, YAP1 and EGFR were predominantly located on monocytes/macrophages, Treg and exhaustive CD8 T cell, and are involved in M2 polarization within the TME of patients with primary and metastatic NSCLC which further implied gene's role in remodeling the tumor immune microenvironment. A molecular-docking analysis revealed that NLOC-015A bound to YAP1, EGFR, MAP kinase/extracellular signal-related kinase kinase 1 (MEK1), and mTOR with strong binding efficacies ranging -8.4 to -9.50 kcal/mol. Interestingly, compared to osimertinib, NLOC-015 bound with higher efficacy to the tyrosine kinase (TK) domains of both T790M and T790M/C797S mutant-bearing EGFR. Our in vitro studies and sequencing analysis revealed that NLOC-015A inhibited the proliferation and oncogenic phenotypes of NSCLC cell lines with concomitant downregulation of expression levels of mTOR, EGFR, YAP1, and MEK1 signaling network. We, therefore, suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR, mTOR/NF-kappaB, YAP1, MEK1 in NSCLC. CI - Copyright (c) 2022 Lawal, Wu and Huang. FAU - Lawal, Bashir AU - Lawal B AD - Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan. AD - Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. FAU - Wu, Alexander T H AU - Wu ATH AD - TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. AD - The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. AD - Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. AD - Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. FAU - Huang, Hsu-Shan AU - Huang HS AD - Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan. AD - Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. AD - Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. AD - School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. AD - PhD Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220517 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology MH - Drug Resistance, Neoplasm MH - ErbB Receptors/metabolism MH - Humans MH - *Lung Neoplasms/drug therapy/genetics/pathology MH - Mutation MH - Protein Kinase Inhibitors/pharmacology/therapeutic use MH - Sequence Analysis, RNA MH - TOR Serine-Threonine Kinases/genetics MH - Tumor Microenvironment/genetics PMC - PMC9152008 OTO - NOTNLM OT - NLOC-15A OT - epidermal growth factor receptor (EGFR) OT - hippo pathway OT - multitarget small molecule OT - non-small-cell lung cancer (NSCLC) COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/06/04 06:00 MHDA- 2022/06/07 06:00 PMCR- 2022/01/01 CRDT- 2022/06/03 02:18 PHST- 2022/02/09 00:00 [received] PHST- 2022/04/15 00:00 [accepted] PHST- 2022/06/03 02:18 [entrez] PHST- 2022/06/04 06:00 [pubmed] PHST- 2022/06/07 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.872470 [doi] PST - epublish SO - Front Immunol. 2022 May 17;13:872470. doi: 10.3389/fimmu.2022.872470. eCollection 2022.