Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule
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 c...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.872470/full |
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| author | Bashir Lawal Bashir Lawal Alexander T. H. Wu Alexander T. H. Wu Alexander T. H. Wu Alexander T. H. Wu Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang |
| author_facet | Bashir Lawal Bashir Lawal Alexander T. H. Wu Alexander T. H. Wu Alexander T. H. Wu Alexander T. H. Wu Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang |
| author_sort | Bashir Lawal |
| collection | DOAJ |
| description | 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-κB, YAP1, MEK1 in NSCLC. |
| first_indexed | 2024-04-12T11:49:11Z |
| format | Article |
| id | doaj.art-365c620e9ec846b996039d3be9cb6088 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T11:49:11Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-365c620e9ec846b996039d3be9cb60882022-12-22T03:34:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.872470872470Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small MoleculeBashir Lawal0Bashir Lawal1Alexander T. H. Wu2Alexander T. H. Wu3Alexander T. H. Wu4Alexander T. H. Wu5Hsu-Shan Huang6Hsu-Shan Huang7Hsu-Shan Huang8Hsu-Shan Huang9Hsu-Shan Huang10Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, TaiwanGraduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanTMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, TaiwanThe PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanClinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, TaiwanGraduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanPh.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, TaiwanGraduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanGraduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanSchool of Pharmacy, National Defense Medical Center, Taipei, TaiwanPhD Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, TaiwanLung 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-κB, YAP1, MEK1 in NSCLC.https://www.frontiersin.org/articles/10.3389/fimmu.2022.872470/fullNLOC-15Amultitarget small moleculenon-small-cell lung cancer (NSCLC)epidermal growth factor receptor (EGFR)hippo pathway |
| spellingShingle | Bashir Lawal Bashir Lawal Alexander T. H. Wu Alexander T. H. Wu Alexander T. H. Wu Alexander T. H. Wu Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang Hsu-Shan Huang Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule Frontiers in Immunology NLOC-15A multitarget small molecule non-small-cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) hippo pathway |
| title | Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule |
| title_full | Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule |
| title_fullStr | Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule |
| title_full_unstemmed | Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule |
| title_short | Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule |
| title_sort | leveraging bulk and single cell rna sequencing data of nsclc tumor microenvironment and therapeutic potential of nloc 15a a novel multi target small molecule |
| topic | NLOC-15A multitarget small molecule non-small-cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) hippo pathway |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.872470/full |
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