Multi-Omics Data Analysis of Gene Expressions and Alterations, Cancer-Associated Fibroblast and Immune Infiltrations, Reveals the Onco-Immune Prognostic Relevance of STAT3/CDK2/4/6 in Human Malignancies

Lawal, Bashir; Lin, Li; Lee, Jih Chin; Chen, Jia Hong; Bekaii‐Saab, Tanios; Wu, Alexander T.H.; Ho, Ching Liang

doi:10.3390/cancers13050954

Cited by 36 publications

(45 citation statements)

References 77 publications

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“…Several potential molecular targets exist for exploring the dysregulation of signaling pathways of cancer cells (10)(11)(12). Growth factors, including epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF), and vascular endothelial growth factor (VEGF), are compact molecules that play important roles in regulating cellular communication, growth and differentiation, proliferation, survival, migration, and metastasis of cancer cells (13,14).…”

Section: Introductionmentioning

confidence: 99%

mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2′,4′-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications

et al. 2021

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BackgroundThe application of computational and multi-omics approaches has aided our understanding of carcinogenesis and the development of therapeutic strategies. NSC765598 is a novel small molecule derivative of salicylanilide. This study aims to investigate the ligand-protein interactions of NSC765598 with its potential targets and to evaluate its anticancer activities in vitro.MethodsWe used multi-computational tools and clinical databases, respectively, to identify the potential drug target for NSC765598 and analyze the genetic profile and prognostic relevance of the targets in multiple cancers. We evaluated the in vitro anticancer activities against the National Cancer Institute 60 (NCI60) human tumor cell lines and used molecular docking to study the ligand-protein interactions. Finally, we used the DTP-COMPARE algorithm to compare the NSC765598 anticancer fingerprints with NCI standard agents.ResultsWe identified mammalian target of rapamycin (mTOR)/epidermal growth factor receptor (EGFR)/inducible nitric oxide synthase (iNOS)/mitogen-activated protein 2 kinase 1 (MAP2K1)/fibroblast growth factor receptor (FGFR)/transforming growth factor-β1 (TGFB1) as potential targets for NSC765598. The targets were enriched in cancer-associated pathways, were overexpressed and were of prognostic relevance in multiple cancers. Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non–small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered. NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI50) = 1.12–3.95 µM; total growth inhibition (TGI) = 3.72–16.60 μM), leukemia (GI50 = 1.20–3.10 µM; TGI = 3.90–12.70 μM), melanoma (GI50 = 1.45–3.59 µM), and renal cancer (GI50 = 1.38–3.40 µM; TGI = 4.84–13.70 μM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598. Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of π-interactions, with higher preferences for EGFR (ΔG = −11.0 kcal/mol), NOS2 (ΔG = −11.0 kcal/mol), and mTOR (ΔG = −8.8 kcal/mol). NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.ConclusionNSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.

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Section: Introductionmentioning

confidence: 99%

mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2′,4′-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications

et al. 2021

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“…The development of targeted therapies for breast cancer is impeded by the heterogeneity of cancer cells which enhances their proliferation and invasive phenotypes and regulates their responsiveness to therapies 50 , 51 . In addition, the molecular targets of current therapies, such as ER/PI3K/Akt, human epidermal growth factor receptor 2 (HER2), mammalian target of rapamycin (mTOR), and CDK4/CDK6, exhibit considerable intra- and inter-patient variations in their expression levels 28 , 29 . In line with previous studies, our analysis of clinical data revealed that CDK2/CDK4 are overexpressed in breast cancer patients and contribute to tumor progression, metastasis, invasive phenotypes and non-responsiveness to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Our mechanistic study further revealed that BC-N102 treatment led to time-course and dose-dependent arrest of the cell cycle at G0/G1 phase with concomitant downregulation of ER, PI3K, p-ERK, p-AKT, cyclin D1, CDK2, and CDK4. Cyclin-dependent kinases play an important role in cell cycle progression and tumorigenesis in various cancers 28 . In line with our observation, a number of studies have associated the inhibition of CDKs to cell cycle arrest 52 , 53 .…”

Section: Discussionmentioning

confidence: 99%

BC-N102 suppress breast cancer tumorigenesis by interfering with cell cycle regulatory proteins and hormonal signaling, and induction of time-course arrest of cell cycle at G1/G0 phase

Lawal¹,

Kuo²,

Wu³

et al. 2021

Int. J. Biol. Sci.

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Mechanisms of breast cancer progression and invasion, often involve alteration of hormonal signaling, and upregulation and/or activation of signal transduction pathways that input to cell cycle regulation . Herein, we describe a rationally designed first-in-class novel small molecule inhibitor for targeting oncogenic and hormonal signaling in ER-positive breast cancer. BC-N102 treatment exhibits dose-dependent cytotoxic effects against ER+ breast cancer cell lines. BC-N102 exhibited time course- and dose-dependent cell cycle arrest via downregulation of the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-Akt, CDK2, and CDK4 while increasing p38 mitogen-activated protein kinase (MAPK), and mineralocorticoid receptor (MR) signaling in breast cancer cell line. In addition, we found that BC-N102 suppressed breast cancer tumorigenesis in vivo and prolonged the survival of animals. Our results suggest that the proper application of BC-N102 may be a beneficial chemotherapeutic strategy for ER+ breast cancer patients.

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“…Deregulated CDK activation causes unscheduled proliferation along with chromosomal and genomic instability [ 12 ]. CDK-cyclin complexes continue either proliferation or unplanned re-entry into the cell cycle, which is frequently observed with deregulation seen in certain CDK-cyclin complexes [ 13 ]. Specific CDKs are required by tumor cells for progression; hence, therapeutic strategies responsible for CDK inhibition should be taken into account depending on these particular criteria [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1

Khedkar

Wang

Yadav

et al. 2021

IJMS

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Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease’s pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI50 = 1.6 µM~1.82 µM and TGI50 = 3.5 µM~3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma.

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Multi-Omics Data Analysis of Gene Expressions and Alterations, Cancer-Associated Fibroblast and Immune Infiltrations, Reveals the Onco-Immune Prognostic Relevance of STAT3/CDK2/4/6 in Human Malignancies

Cited by 36 publications

References 77 publications

mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2′,4′-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications

mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2′,4′-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications

BC-N102 suppress breast cancer tumorigenesis by interfering with cell cycle regulatory proteins and hormonal signaling, and induction of time-course arrest of cell cycle at G1/G0 phase

In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1

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