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研究生:Bashir Lawal
研究生(外文):LAWAL, BASHIR
論文名稱:Pharmacoinformatic analysis and preclinical evaluation of a novel first-in class onco-immunotherapeutic small molecule for the treatment of non-small-cell lung cancer (NSCLC)
論文名稱(外文):Pharmacoinformatic analysis and preclinical evaluation of a novel first-in class onco-immunotherapeutic small molecule for the treatment of non-small-cell lung cancer (NSCLC)
指導教授:黃 旭山吳 駿翃蕭宏昇
指導教授(外文):HUANG, HSU-SHANWU, ALEXANDER T.H.HSIAO, MICHAEL
口試委員:黃雯華賈淑敏 所長 教授李 崑豪楊 培銘蕭宏昇吳 駿翃黃 旭山
口試委員(外文):WENDY, HWANG-VERSLUESKA, SHUK-MANLEE, KUEN-HAURYANG, PEI-MINGHSIAO, MICHAEL (Co-advisor)WU, ALEXANDER T.H. (Co-advisor)HUANG, HSU-SHAN (Advisor)
口試日期:2022-05-31
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:癌症生物學與藥物研發博士學位學程
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:英文
論文頁數:121
中文關鍵詞:NLOC-15Aepidermal growth factor receptor (EGFR)multitarget small moleculenon-small-cell lung cancer (NSCLC)Hippo pathway
外文關鍵詞:NLOC-15Aepidermal growth factor receptor (EGFR)multitarget small moleculenon-small-cell lung cancer (NSCLC)Hippo pathway
ORCID或ResearchGate:https://orcid.org/ 0000-0003-0676-5875
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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 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 first-in class 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/MEK1/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, 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 revealed that NLOC-015A inhibited the proliferation and oncogenic properties of NSCLC with concomitant downregulation of EGFR/MAP2K1/mTOR/YAP1 signaling networks. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), c-Myc, and SOX2 in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Interestingly, NLOC-015A synergistically enhanced the anti-NSCLC activities of osimertinib both in vitro and in vivo models. 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.
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 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 first-in class 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/MEK1/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, 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 revealed that NLOC-015A inhibited the proliferation and oncogenic properties of NSCLC with concomitant downregulation of EGFR/MAP2K1/mTOR/YAP1 signaling networks. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), c-Myc, and SOX2 in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Interestingly, NLOC-015A synergistically enhanced the anti-NSCLC activities of osimertinib both in vitro and in vivo models. 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.
Content
Titles Pages
Abstract…………………………………………………………………………………. I
Acknowledgements……………………………………………………………………... III
Content………………………………………………………………………………….. IV
List of tables…………………………………………………………………………….. VIII
List of figures…………………………………………………………………………… IX
List of abbreviations…………………………………………………………………….. XII
CHAPTER ONE………………………………………………………………………... 1
1.0 Introduction…………………………………………………………………………. 1
1.1 Human Lung……………………………………………………………………........ 1
1.2 Lung cancer ………………………………………………………………………… 1
1.3 Lung cancer classification………………………………………………………...... 3
1.4 Stage grouping of lung cancer………………………………………………………. 3
1.5 Global prevalence of lung cancer……………………………………………………. 4
1.5.1 Tobacco consumption and incidence of lung cancer……………………………… 5
1.6 Lung cancer survival……………………………………………………………....... 7
1.7 Mechanisms and pathophysiology of lung cancer………………………………...... 7
1.8 Genetic alterations and pathways…………………………………………………… 8
1.9 Epidermal growth factor receptor (EGFR) and EGFR-tyrosine kinase inhibitors (TKIs) …………………………………………………………………………………... 10
1.10 Third Generation EGFR-tyrosine kinase inhibitor………………………………… 12
1.11 Rational of the study……………………………………………………………….. 13
1.12 Specific aims of the Study…………………………………………………………. 15
CHAPTER TWO……………………………………………………………………….. 18
2.0 Materials and methods………………………………………………. …………….. 18
2.1Differential expression and lung cancer context-specific network interactions analysis……………………………………………………………………………......... 18
2.2 Differential phosphorylation analysis………………………………………………. 18
2.3 Prognostic analysis………………………………………………………………….. 18
2.4 Tumor immune infiltration analysis……………………………………………………….. 19
2.5Leveraging Single-Cell RNA Sequencing (scRNA-seq) datasets for tumor immune microenvironment of primary and metastatic sites of NSCLC……………………….. 19
2.6 Analysis of Gene association with drug resistance…………………………………. 20
2.7 Synthesis of NLOC_015A…………………………………………………………... 20
2.8In silico evaluation of the drug likeness, pharmacokinetics (PKs), and physicochemical properties of the NLOC-series……………………………………………. 21
2.9 Molecular docking…………………………………………………………………... 22
2.10 Cell lines and culture……………………………………………………………… 23
2.11 Cell-viability assay ……………………………………………………………...... 23
2.12 In vitro antiproliferative analysis of NLOC series against NCI-60 cell lines…….. 24
2.13 NCI-DTP-COMPARE analysis of NLOC_015A anticancer fingerprints………… 24
2.14 Cell-migration and invasion assays……………………………………………….. 25
2.15 Colony-formation assay…………………………………………………………… 25
2.16Tumor Sphere Formation Assay………………………………………………………... 26
2.17 Western blot analysis………………………………………………………………. 26
2.18 RNA sequencing analysis…………………………………………………………. 27
2.19 Determination of the maximum tolerated dose (MTD) of NLOC_015A………..... 27
2.20 In vivo studies……………………………………………………………………… 27
2.21 Analysis of hematological and parameters…………….………………………….. 28
2.22 Statistical analysis…………………………………………………………………. 29
CHAPTER THREE…………………………………………………………………….. 30
3.0 Results……………………………………………………………………………..... 30
3.1 Dysregulation of the EGFR/MEK1/mTOR/TEAD1/YAP1 signaling axis is associated with progression and worse prognoses of NSCLC…………………………. 30
3.2 Genetic alterations of EGFR/MEK1/mTOR/TEAD1/YAP1 mediate other oncogenic interactions and worse prognoses of NSCLC cohorts………………………………….. 31
3.3 EGFR/MEK1/mTOR/TEAD1/YAP1 mediate lung cancer-specific activation of onco-functional molecules and therapeutic responses. ……………………………... 32
3.4 EGFR/MEK1/mTOR/TEAD1/YAP1 could mediate invasive tumor phenotypes and worse prognoses of NSCLC cohorts via a mechanism involving both T-cell exclusion and dysfunctional phenotypes…………………………………………… 32
3.5 Single-cell RNA sequencing (scRNA-seq) datasets revealed the abundance and immunosuppressive role of EGFR/MEK1/MTOR/TEAD1/YAP1 within tumor microenvironment of primary and metastatic NSCLC………………………………. 33
3.6 Rationale for structurally guided pharmacophore hybridization strategy for the design and synthesis of NLOC- series of compounds…………………………………. 35
3.7 NLOC exhibited drug-like and good ADMET pharmacokinetic properties……… 36
3.8 In silico structural-activity based profiling strongly suggest the potential of NLOC_015A for the treatment of lung cancer and associated inflammatory condition…………………………………………………………………………….... 39
3.9 Screening and selection of first-in class compound with higher efficacy against lung cancer………………………………………………………..…………………… 40
3.10 NCI-DTP COMPARE analysis of revealed that NLOC_015A shared similar antitumor fingerprint with NCI-mechanistic mechanistic of EGFR/PI3K/AKT/mTOR signaling network…………………………………………………………………….... 41
3.11 Molecular Docking simulation demonstrated high target binding affinities and potential of NSC828788 (NLOC_015A) for targeting the YAP1/EGFR/MEK1/mTOR signaling network……………………………………………………………………… 42
3.12 NL0C-015A compromised the cell viability, migratory, colony formation and invasive phenotypes of NSCLC via inhibition of the EGFR/MEK1/mTOR/NF-Κb/STAT3 and YAP1 signaling pathways…………………………………………..… 42
3.13 NL0C-015A inhibited the stemness phenotype of NSCLC ability NSCLC via inhibition ALDH/C-MYC/SOX2……………………………………………………… 43
3.14 NL0C-015A synergistically enhanced the anti-tumorigenic activities of osimertinib in NSCLC cells………………………………………………………….… 44
3.15 NL0C-015A activate Hippo signaling pathways to attenuate NSCLC cell growth 44
3.16 In vivo analysis of the maximum tolerated dose (MTD) of NLOC_015A in mice…………………………………………………………………………………..…. 45
3.17 NLOC_015A suppressed tumorigenesis and enhanced the in vivo efficacy of osimertinib in a xenograft model of NSCLC…………………………………………... 46
3.18 NLOC_015A attenuated biochemical and hematological alterations in NSCLC tumor bearing mice…………………………………………………………………....... 46
CHAPTER FOUR………………………………………………………………………. 48
4.0 Discussion…………………………………………………………………………... 48
4.1 Conclusions…………………………………….…………………………………… 53
CHAPTER FIVE……………………………………………………………………….. 54
5.0 Ongoing and future studies…………………………………………………………. 54
5.1 Establishment of drug induced osimertinib resistance NSCLC and evaluation of therapeutic efficacy of NLOC-O15A on the OSM-resistant variant of NSCLC…….…. 54
5.2 Development of EGFR C797S Knock-in by CRISPR/Cas9 genome editing………. 54
5.3 Preclinical investigation of antitumor properties of NLOC_015A in EGFR-C797S_KI bearing mice………………………………………………………………… 55
5.4 Functional and mechanistic evaluation of the role of YAP1/mTOR/EGFR/MEK1 in mediating M2 polarisation of TAM and evaluate the immune-therapeutic efficacy of NLOC_015A……………………………………………………………………….…… 56
5.5 Development of three-dimensional (3D) tumoroids from NSCLC lines and stromal cells for the evaluation of immunotherapeutic potential of NLOC_015A………............. 58
References…………………………………………………………………………........ 59

List of tables
Tables Page
Table 1: Stage groupings for non-small-cell lung cancer……………………………….… 73
Table 2: Predicted drug likeness and pharmacokinetic properties of members of the NLOC- series of niclosamide derivatives…………………………………………….….. 74
Table 3: In silico structural-activity relationship profile of NLOC_015A based on PASS (prediction of activity spectra for substances) algorithm………………………………… 76
Table 4: Specific anti-cancer profiling of NLOC_015A against common cancer cell lines based on PASS (prediction of activity spectra for substances) algorithm……….… 77
Table 5: In vitro Anti-proliferative effect of the 12 structurally related small molecule derivatives of niclosamide against the NCI-60 human tumor cell lines…………………. 78
Table 6: The half maximal inhibitory concentrations (IC50) of structurally related small molecule derivatives of niclosamide against the 9 cell lines subsets of human non-small cell lung cancer……………………………………………………………………..…… 82
Table 7: NCI synthetic compounds and investigational drugs sharing similar anti-cancer and mechanistic fingerprints with NLOC_015A………………………………...……… 83
Table8:-Docking profile of NSC828788 (NLOC_015A) with YAP1/EGFR/MEK1/mTOR………………………………………………………...… 84
Table 9: Maximum tolerated dose (MTD) and acute toxicity profile of NLOC_015A…. 85
Table 10: Effect of NLOC_015A treatment on hematological parameters of NSCLC tumor bearing mice. ……………………………………………………………………... 86

List of figures
Figures Pages
Figure 1: Anatomy and physiology of the lungs…………………………………………. 87
Figure 2: Addition to nicotine, smoke from tobacco, carcinogens, and the pathogenesis of lung cancer. …………………………………………………………………………... 88
Figure 3: Resistance mechanisms EGFR-TKI………………………………………...… 89
Figure 4: Lung cancer classification. ………………………………………………….… 90
Figure 5: Region-specific incidence age-standardized rates by sex for lung cancer among men and women in 2020. ……………………………………………………….. 91
Figure 6: GLOBOCAN 2020 Cancer Death by Country………………………..……….. 92
Figure 7: Genetic adaptation in NSCLC…………………………………….………...… 93
Figure 8: Implications of EGFR and HER2 mutations………………….…………...… 94
Figure 9:Dysregulation of the EGFR/MEK1/mTOR/YAP1 signaling axis is associated with the progression and worse prognoses of NSCLC…….………………………….... 95
Figure 10: Genetic alterations EGFR/MEK1/mTOR/TEAD1/YAP1 mediate other oncogenic interactions and produce worse prognoses of non-small-cell lung cancer (NSCLC) cohorts………………………………………………………….…………… 97
Figure 11: EGFR/MEK1/mTOR/TEAD1/YAP1 mediate lung cancer-specific activation of onco-functional molecules and therapeutic responses………….…………………… 98
Figure 12: EGFR/MEK1/MTOR/TEAD1/YAP1 is hypomethylated and exhibited high copy number alterations with a consequent negative impact on the levels of active CTL within the TME of NSCLC…………………………………………………………….. 99
Figure 13: EGFR/MEK1/mTOR/TEAD1/YAP1 could mediate invasive tumor phenotypes and worse prognoses of non-small-cell lung cancer (NSCLC) cohorts via mechanisms involving both T-cell exclusion and dysfunctional phenotypes……………………………………………………………………………... 100
Figure 14: Single cell sequencing profiling of EGFR/MEK1/MTOR/TEAD1/YAP1 in tumor microenvironment of primary NSCLC………………………………………….. 101
Figure 15: Single cell sequencing profiling of EGFR/MEK1/MTOR/TEAD1/YAP1 in tumor microenvironment of metastatic NSCLC…………………………..…………... 102
Figure 16: EGFR/MEK1/MTOR/TEAD1/YAP1 induced macrophage polarization (A) Bar plot of expression levels of EGFR/MEK1/MTOR/TEAD1/YAP1 at different macrophage state. (B) Enrichment Heatmap of the gene set expression in immune cell (Macrophage-monocyte) at single cell resolution. ……………………………...……... 103
Figure 17: Structurally guided pharmacophore hybridization and scaffold-hopping strategy for the design and development of NLOC compounds……………… 104
Figure 18: Modeling of membrane permeation and the ability to serve as a P-glycoprotein (P-gp) substrate by members of the NLOC- series………………………. 105
Figure 19: In vitro Anti-proliferative effect of the 12 structurally related small molecule derivatives of niclosamide against the 9 cell lines subsets of human non-small cell lung cancer. ……………………………………………………………………………….… 106
Figure 20: High throughput in vitro anti-cancer screening of NLOC_015A against the 60 cancer cell line of the US-NCI-DTP…………………………………………..…….. 107
Figure 21: Molecular docking simulation of NSC828788 (NLOC_015A) demonstrated interactions with YAP1/MEK1/mTOR………………………………………………… 108
Figure 22: The 2-D view of NLOC_015A (NSC-828788) interaction with (A) T790M-EGFR (B) T790M/C797S-EGFR…………………………………………….................. 109
Figure 23: NL0C-015A inhibited the cell viability and oncogenic phenotypes of non-small-cell lung cancer (NSCLC) by modulating of the YAP1/EGFR/MEK/mT0R signaling axis. ………………………….……………………………………………… 110
Figure 23_E: NL0C-015A inhibited the invasiveness of non-small-cell lung cancer (NSCLC) …………………………………………………………………………….… 111
Figure 24: Activity of NL0C-015A on the spheroid-forming abilities of H1299 and H1975 cells…………………………………………………………………………….. 112
Figure 25: NL0C-015A synergistically enhanced the in vitro antitumorigenic effect of osimertinib in the non-small cell lung cancer (NSCLC)……………………………..…. 113
Figure 26: NL0C-015A exhibited anti-non-small-cell lung cancer (NSCLC) activities via modulation of Hippo, EGFR-MEK, and NF-κB-TOR pathways in NSCLC. …………………………………………………………………………………………. 114
Figure 27: NLOC_015A suppressed tumorigenesis and enhanced the in vivo efficacy of osimertinib in a xenograft model of (NSCLC) ………………………………..…….. 115
Figure 28: Effect of NLOC_015A treatment on hematological parameters of NSCLC tumor bearing mice. ………………………………………………………………….... 116
Figure 29: Schematic representation of the mechanism of action of NLOC_015A….… 117
Figure 30: NLOC_015A demonstrated a preliminary therapeutic efficacy for the treatment of OSM-resistance NSCLC. ………………………………………………… 118
Figure 31: EGFR-CRISPR/Cas9 genome editing of H1975 cell line………………….. 119
Figure 32: Overall design for in vivo evaluation of NLOC_015A in osimertinib resistance EGFR-C797S bearing NSCLC. …………………………………………....... 120
Figure 33: Development of three-dimensional (3D) tumoroids from lung cancer cell lines and stromal cells…………………………………………………………............... 121


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