Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives
Genetic and environmental factors play important roles in cancer progression, metastasis, and drug resistance. Herein, we used a multiomics data analysis to evaluate the predictive and prognostic roles of genetic and epigenetic modulation of c-MET (hepatocyte growth factor receptor)/epidermal growth...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.691234/full |
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| author | Bashir Lawal Bashir Lawal Yu-Chi Wang 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 Yu-Chi Wang 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 | Genetic and environmental factors play important roles in cancer progression, metastasis, and drug resistance. Herein, we used a multiomics data analysis to evaluate the predictive and prognostic roles of genetic and epigenetic modulation of c-MET (hepatocyte growth factor receptor)/epidermal growth factor receptor (EGFR) in colorectal cancer (CRC). First, we found that overexpressions of c-MET/EGFR were associated with the infiltration of tumor immune cells and cancer-associated fibroblasts, and were of prognostic relevance in CRC cohorts. We also observed that genetic alterations of c-MET/EGFR in CRC co-occurred with other gene alterations and were associated with overexpression of messenger (m)RNA of some cancer hallmark proteins. More specifically, DNA-methylation and somatic copy number alterations of c-MET/EGFR were associated with immune infiltration, dysfunctional T-cell phenotypes, and poor prognoses of the cohorts. Moreover, we describe two novel gefitinib-inspired small molecules derivatives of 3-phenyl-2H-benzo[e] [1,3]-oxazine-2,4(3H)-dione, NSC777205 and NSC777207, which exhibited wide-spectrum antiproliferative activities and selective cytotoxic preference for drug-sensitive and multidrug-resistant melanoma, renal, central nervous system, colon, and non-small cell lung cancer cell lines. We further provided in silico mechanistic evidence implicating c-MET/EGFR/phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibition in anticancer activities of those compounds. Our overall structure-activity relationship study revealed that the addition of an –OCH3 group to salicylic core of NSC777207 was not favorable, as the added moiety led to overall less-favorable drug properties as well as weaker anticancer activities compared to the properties and activities demonstrated by NSC777205 that has no –OCH3 substituent group. Further in vitro and in vivo analyses in tumor-bearing mice are ongoing in our lab to support this claim and to unravel the full therapeutic efficacies of NSC777205 and NSC777207 in CRC. |
| first_indexed | 2024-12-16T20:56:54Z |
| format | Article |
| id | doaj.art-681b060fd7b342cbb7e12b6a7b711238 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-16T20:56:54Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-681b060fd7b342cbb7e12b6a7b7112382022-12-21T22:16:36ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-08-011210.3389/fphar.2021.691234691234Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione DerivativesBashir Lawal0Bashir Lawal1Yu-Chi Wang2Alexander T. H. Wu3Alexander T. H. Wu4Alexander T. H. Wu5Alexander T. H. Wu6Hsu-Shan Huang7Hsu-Shan Huang8Hsu-Shan Huang9Hsu-Shan Huang10Hsu-Shan Huang11PhD Program for Cancer Molecular 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, TaiwanDepartment of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanTMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, TaiwanThe PhD Program of Translational Medicine, College of 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, TaiwanPhD Program for Cancer Molecular 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 Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, TaiwanGenetic and environmental factors play important roles in cancer progression, metastasis, and drug resistance. Herein, we used a multiomics data analysis to evaluate the predictive and prognostic roles of genetic and epigenetic modulation of c-MET (hepatocyte growth factor receptor)/epidermal growth factor receptor (EGFR) in colorectal cancer (CRC). First, we found that overexpressions of c-MET/EGFR were associated with the infiltration of tumor immune cells and cancer-associated fibroblasts, and were of prognostic relevance in CRC cohorts. We also observed that genetic alterations of c-MET/EGFR in CRC co-occurred with other gene alterations and were associated with overexpression of messenger (m)RNA of some cancer hallmark proteins. More specifically, DNA-methylation and somatic copy number alterations of c-MET/EGFR were associated with immune infiltration, dysfunctional T-cell phenotypes, and poor prognoses of the cohorts. Moreover, we describe two novel gefitinib-inspired small molecules derivatives of 3-phenyl-2H-benzo[e] [1,3]-oxazine-2,4(3H)-dione, NSC777205 and NSC777207, which exhibited wide-spectrum antiproliferative activities and selective cytotoxic preference for drug-sensitive and multidrug-resistant melanoma, renal, central nervous system, colon, and non-small cell lung cancer cell lines. We further provided in silico mechanistic evidence implicating c-MET/EGFR/phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibition in anticancer activities of those compounds. Our overall structure-activity relationship study revealed that the addition of an –OCH3 group to salicylic core of NSC777207 was not favorable, as the added moiety led to overall less-favorable drug properties as well as weaker anticancer activities compared to the properties and activities demonstrated by NSC777205 that has no –OCH3 substituent group. Further in vitro and in vivo analyses in tumor-bearing mice are ongoing in our lab to support this claim and to unravel the full therapeutic efficacies of NSC777205 and NSC777207 in CRC.https://www.frontiersin.org/articles/10.3389/fphar.2021.691234/fullcolorectal cancergenetic and epigenetic alterationscancer-associated fibroblastimmune infiltrationsmall moleculeNSC777205 |
| spellingShingle | Bashir Lawal Bashir Lawal Yu-Chi Wang 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 Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives Frontiers in Pharmacology colorectal cancer genetic and epigenetic alterations cancer-associated fibroblast immune infiltration small molecule NSC777205 |
| title | Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives |
| title_full | Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives |
| title_fullStr | Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives |
| title_full_unstemmed | Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives |
| title_short | Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives |
| title_sort | pro oncogenic c met egfr biomarker signatures of the tumor microenvironment are clinical and therapy response prognosticators in colorectal cancer and therapeutic targets of 3 phenyl 2h benzo e 1 3 oxazine 2 4 3h dione derivatives |
| topic | colorectal cancer genetic and epigenetic alterations cancer-associated fibroblast immune infiltration small molecule NSC777205 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.691234/full |
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