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1
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Zheng MY, Lin YT, Kuo YS, Lin YJ, Kuo MH, Huang TW, Shieh YS, Huang Y, Chou YT. Cytokine and epigenetic regulation of CEACAM6 mediates EGFR-driven signaling and drug response in lung adenocarcinoma. NPJ Precis Oncol 2025; 9:115. [PMID: 40263546 PMCID: PMC12015248 DOI: 10.1038/s41698-025-00910-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 04/10/2025] [Indexed: 04/24/2025] Open
Abstract
CEACAM family proteins have been extensively studied as cell adhesion molecules, yet the biological and clinical significance of CEACAM6 remains relatively unexplored. Our research identifies a significant increase in CEACAM6 expression in lung adenocarcinoma, particularly correlating with EGFR mutation status. In EGFR-mutated lung cancer cells, CEACAM6 knockdown induced apoptosis and reduced p-ERK1/2 signaling downstream of EGFR. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) decreased CEACAM6 levels, leading to TKI-resistant lung cancer cells that exhibited reduced p-ERK1/2 and increased epithelial-mesenchymal transition (EMT) characteristics. Co-immunoprecipitation assays revealed an interaction between CEACAM6 and EGFR. Although CEACAM6 expression was lost in EGFR-TKI resistant cells, its re-expression stabilized EGFR and increased sensitivity to EGFR-TKIs. TGF-β treatment, which induced EMT, also decreased CEACAM6 expression and improved EGFR-TKI resistance. Further analysis showed that EGFR-TKI resistant lung cancer cells had lower H3K27ac epigenetic modification levels at the CEACAM6 locus than EGFR-TKI sensitive cells. Treatment with HDAC1/2 inhibitors in EGFR-TKI sensitive cells reduced CEACAM6 expression, induced EMT and TGF-β-ligand/receptor gene expression, and enhanced EGFR-TKI resistance. These data highlight the crucial role of CEACAM6 in maintaining oncogenic EGFR signaling and its regulation by cytokine stimulation and epigenetic modification, influencing EGFR-TKI sensitivity. Our findings underscore CEACAM6's potential as a valuable biomarker in EGFR-driven lung adenocarcinoma and its intricate involvement in EGFR-related pathways.
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Affiliation(s)
- Ming-Yi Zheng
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Yen-Ting Lin
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Yen-Shou Kuo
- Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yen-Ju Lin
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Ming-Han Kuo
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Tsai-Wang Huang
- Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Shing Shieh
- Department of Oral Diagnosis & Pathology, Tri-Service General Hospital, Taipei, Taiwan
| | - Yenlin Huang
- Department of Medicine, National Tsing Hua University, Hsinchu, Institute of Stem Cell and Translational Cancer Research and Department of Anatomic Pathology, Chang Gung Memorial Hospital Linkou, Taoyuan, Taiwan
| | - Yu-Ting Chou
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
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2
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Gottumukkala SB, Palanisamy A. Non-small cell lung cancer map and analysis: exploring interconnected oncogenic signal integrators. Mamm Genome 2025:10.1007/s00335-025-10110-6. [PMID: 39939487 DOI: 10.1007/s00335-025-10110-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 01/29/2025] [Indexed: 02/14/2025]
Abstract
Non-Small Cell lung cancer (NSCLC) is known for its fast progression, metastatic potency, and a leading cause of mortality globally. At diagnosis, approximately 30-40% of NSCLC patients already present with metastasis. Epithelial to mesenchymal transition (EMT) is a developmental program implicated in cancer progression and metastasis. Transforming Growth Factor-β (TGFβ) and its signalling plays a prominent role in orchestrating the process of EMT and cancer metastasis. In present study, a comprehensive molecular interaction map of TGFβ induced EMT in NSCLC was developed through an extensive literature survey. The map encompasses 394 species interconnected through 554 reactions, representing the relationship and complex interplay between TGFβ induced SMAD dependent and independent signalling pathways (PI3K/Akt, Wnt, EGFR, JAK/STAT, p38 MAPK, NOTCH, Hypoxia). The map, built using Cell Designer and compliant with SBGN and SBML standards, was subsequently translated into a logical modelling framework using CaSQ and dynamically analysed with Cell Collective. These analyses illustrated the complex regulatory dynamics, capturing the known experimental outcomes of TGFβ induced EMT in NSCLC including the co-existence of hybrid EM phenotype during transition. Hybrid EM phenotype is known to contribute for the phenotypic plasticity during metastasis. Network-based analysis identified the crucial network level properties and hub regulators, while the transcriptome-based analysis cross validated the prognostic significance and clinical relevance of key regulators. Overall, the map developed and the subsequent analyses offer deeper understanding of the complex regulatory network governing the process of EMT in NSCLC.
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Affiliation(s)
- Sai Bhavani Gottumukkala
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, Telangana, India
| | - Anbumathi Palanisamy
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, Telangana, India.
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3
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Glaviano A, Lau HSH, Carter LM, Lee EHC, Lam HY, Okina E, Tan DJJ, Tan W, Ang HL, Carbone D, Yee MYH, Shanmugam MK, Huang XZ, Sethi G, Tan TZ, Lim LHK, Huang RYJ, Ungefroren H, Giovannetti E, Tang DG, Bruno TC, Luo P, Andersen MH, Qian BZ, Ishihara J, Radisky DC, Elias S, Yadav S, Kim M, Robert C, Diana P, Schalper KA, Shi T, Merghoub T, Krebs S, Kusumbe AP, Davids MS, Brown JR, Kumar AP. Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition. J Hematol Oncol 2025; 18:6. [PMID: 39806516 PMCID: PMC11733683 DOI: 10.1186/s13045-024-01634-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Hannah Si-Hui Lau
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Lukas M Carter
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Donavan Jia Jie Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Wency Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Michelle Yi-Hui Yee
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Lina H K Lim
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, 23538, Lübeck, Germany
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, 1081, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017, San Giuliano, Italy
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Tullia C Bruno
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Bin-Zhi Qian
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, W12 0BZ, UK
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Salem Elias
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Saurabh Yadav
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Minah Kim
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Caroline Robert
- Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
- Faculty of Medicine, University Paris-Saclay, Kremlin Bicêtre, Paris, France
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kurt A Schalper
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Tao Shi
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, NY, USA
| | - Simone Krebs
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
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4
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Zhuo L, Guo M, Zhang S, Wu J, Wang M, Shen Y, Peng X, Wang Z, Jiang W, Huang W. Structure-activity relationship study of 1,6-naphthyridinone derivatives as selective type II AXL inhibitors with potent antitumor efficacy. Eur J Med Chem 2024; 265:116090. [PMID: 38169272 DOI: 10.1016/j.ejmech.2023.116090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/08/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024]
Abstract
The role of AXL in various oncogenic processes has made it an attractive target for cancer therapy. Currently, kinase selectivity profiles, especially circumventing MET inhibition, remain a scientific issue of great interest in the discovery of selective type II AXL inhibitors. Starting from a dual MET/AXL-targeted lead structure from our previous work, we optimized a 1,6-naphthyridinone series using molecular modeling-assisted compound design to improve AXL potency and selectivity over MET, resulting in the potent and selective type II AXL-targeted compound 25c. This showed excellent AXL inhibitory activity (IC50 = 1.1 nM) and 343-fold selectivity over the highly homologous kinase MET in biochemical assays. Moreover, compound 25c significantly inhibited AXL-driven cell proliferation, dose-dependently suppressed 4T1 cell migration and invasion, and induced apoptosis. Compound 25c also showed noticeable antitumor efficacy in a BaF3/TEL-AXL xenograft model at well-tolerated doses. Overall, this study presented a potent and selective type II AXL-targeted lead compound for further drug discovery.
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Affiliation(s)
- Linsheng Zhuo
- Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Mengqin Guo
- School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430071, China
| | - Siyi Zhang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Junbo Wu
- Department of Colorectal Surgery, Hengyang Central Hospital, Hengyang, Hunan, 421001, China
| | - Mingshu Wang
- Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan, 430079, China
| | - Yang Shen
- Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xue Peng
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhen Wang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Weifan Jiang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Wei Huang
- Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan, 430079, China.
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5
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Linzer J, Phelps Z, Vummidi S, Lee BYE, Coant N, Haley JD. Mass Spectrometry and Pharmacological Approaches to Measuring Cooption and Reciprocal Activation of Receptor Tyrosine Kinases. Proteomes 2023; 11:20. [PMID: 37368466 PMCID: PMC10304582 DOI: 10.3390/proteomes11020020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/11/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023] Open
Abstract
Receptor tyrosine kinases (RTKs) can show extensive crosstalk, directly and indirectly. Elucidating RTK crosstalk remains an important goal in the clinical combination of anti-cancer therapies. Here, we present mass spectrometry and pharmacological approaches showing the hepatocyte growth factor receptor (MET)-promoting tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) and other membrane receptors in MET-amplified H1993 NSCLC cells. Conversely, in H292 wt-EGFR NSCLC cells, EGFR promotes the tyrosine phosphorylation of MET. Reciprocal regulation of the EGFR and insulin receptor (IR) was observed in the GEO CRC cells, where inhibition of the EGFR drives tyrosine phosphorylation of the insulin receptor. Similarly, in platelet-derived growth factor receptor (PDGFR)-amplified H1703 NSCLC cells, inhibition of the EGFR promotes the tyrosine phosphorylation of the PDGFR. These RTK interactions are used to illustrate basic principles applicable to other RTK signaling networks. More specifically, we focus on two types of RTK interaction: (1) co-option of one RTK by another and (2) reciprocal activation of one receptor following the inhibition of a distinct receptor.
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Affiliation(s)
| | | | | | | | | | - John D. Haley
- Department of Pathology and Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
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6
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Laface C, Maselli FM, Santoro AN, Iaia ML, Ambrogio F, Laterza M, Guarini C, De Santis P, Perrone M, Fedele P. The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Clinical Application of New Therapeutic Strategies. Pharmaceutics 2023; 15:1604. [PMID: 37376053 DOI: 10.3390/pharmaceutics15061604] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/13/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Almost 17% of Western patients affected by non-small cell lung cancer (NSCLC) have an activating epidermal growth factor receptor (EGFR) gene mutation. Del19 and L858R are the most-common ones; they are positive predictive factors for EGFR tyrosine kinase inhibitors (TKIs). Currently, osimertinib, a third-generation TKI, is the standard first-line therapy for advanced NSCLC patients with common EGFR mutations. This drug is also administered as a second-line treatment for those patients with the T790M EGFR mutation and previously treated with first- (erlotinib, gefitinib) or second- (afatinib) generation TKIs. However, despite the high clinical efficacy, the prognosis remains severe due to intrinsic or acquired resistance to EGRF-TKIs. Various mechanisms of resistance have been reported including the activation of other signalling pathways, the development of secondary mutations, the alteration of the downstream pathways, and phenotypic transformation. However, further data are needed to achieve the goal of overcoming resistance to EGFR-TKIs, hence the necessity of discovering novel genetic targets and developing new-generation drugs. This review aimed to deepen the knowledge of intrinsic and acquired molecular mechanisms of resistance to EGFR-TKIs and the development of new therapeutic strategies to overcome TKIs' resistance.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | | | | | - Maria Laura Iaia
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Marigia Laterza
- Division of Cardiac Surgery, University of Bari, 70124 Bari, Italy
| | - Chiara Guarini
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Pierluigi De Santis
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Martina Perrone
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
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7
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Zhou J, Zhang XC, Xue S, Dai M, Wang Y, Peng X, Chen J, Wang X, Shen Y, Qin H, Chen B, Zheng Y, Gao X, Xie Z, Ding J, Jiang H, Wu YL, Geng M, Ai J. SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer. Signal Transduct Target Ther 2023; 8:185. [PMID: 37183231 PMCID: PMC10183461 DOI: 10.1038/s41392-023-01403-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 02/19/2023] [Accepted: 03/05/2023] [Indexed: 05/16/2023] Open
Abstract
Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20-25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-β1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.
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Affiliation(s)
- Ji Zhou
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xu-Chao Zhang
- Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510080, China
| | - Shan Xue
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Mengdi Dai
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Yueliang Wang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xia Peng
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jianjiao Chen
- Department of Neurobiology, Brain Institute, University of Pittsburgh, Pittsburgh, 15213, USA
| | - Xinyi Wang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yanyan Shen
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hui Qin
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Bi Chen
- Department of Respiratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Yu Zheng
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Xiwen Gao
- Department of Respiratory Medicine, Minhang Hospital, Fudan University, Shanghai, 201199, China
| | - Zuoquan Xie
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Jian Ding
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, P. R. China
| | - Handong Jiang
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Yi-Long Wu
- Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510080, China.
| | - Meiyu Geng
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, P. R. China.
| | - Jing Ai
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, P. R. China.
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8
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Nairuz T, Mahmud Z, Manik RK, Kabir Y. Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance. Stem Cell Rev Rep 2023:10.1007/s12015-023-10529-x. [PMID: 37129728 DOI: 10.1007/s12015-023-10529-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2023] [Indexed: 05/03/2023]
Abstract
The term "cancer stem cells" (CSCs) refers to cancer cells that exhibit traits parallel to normal stem cells, namely the potential to give rise to every type of cell identified in a tumor microenvironment. It has been found that CSCs usually develops from other neoplastic cells or non-cancerous somatic cells by acquiring stemness and malignant characteristics through particular genetic modifications. A trivial number of CSCs, identified in solid and liquid cancer, can give rise to an entire tumor population with aggressive anticancer drug resistance, metastasis, and invasiveness. Besides, cancer stem cells manipulate their intrinsic and extrinsic features, regulate the metabolic pattern of the cell, adjust efflux-influx efficiency, modulate different signaling pathways, block apoptotic signals, and cause genetic and epigenetic alterations to retain their pluripotency and ability of self-renewal. Notably, to keep the cancer stem cells' ability to become malignant cells, mesenchymal stem cells, tumor-associated fibroblasts, immune cells, etc., interact with one another. Furthermore, CSCs are characterized by the expression of particular molecular markers that carry significant diagnostic and prognostic significance. Because of this, scientific research on CSCs is becoming increasingly imperative, intending to understand the traits and behavior of cancer stem cells and create more potent anticancer therapeutics to fight cancer at the CSC level. In this review, we aimed to elucidate the critical role of CSCs in the onset and spread of cancer and the characteristics of CSCs that promote severe resistance to targeted therapy.
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Affiliation(s)
- Tahsin Nairuz
- Department of Biochemistry and Molecular Biology, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Rasel Khan Manik
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
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9
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Wang S, Rong R, Yang DM, Fujimoto J, Bishop JA, Yan S, Cai L, Behrens C, Berry LD, Wilhelm C, Aisner D, Sholl L, Johnson BE, Kwiatkowski DJ, Wistuba II, Bunn PA, Minna J, Xiao G, Kris MG, Xie Y. Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer. J Clin Invest 2023; 133:e160330. [PMID: 36647832 PMCID: PMC9843059 DOI: 10.1172/jci160330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 11/08/2022] [Indexed: 01/18/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.
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Affiliation(s)
- Shidan Wang
- Quantitative Biomedical Research Center, The Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ruichen Rong
- Quantitative Biomedical Research Center, The Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Donghan M. Yang
- Quantitative Biomedical Research Center, The Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Junya Fujimoto
- Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Justin A. Bishop
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Shirley Yan
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ling Cai
- Quantitative Biomedical Research Center, The Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Carmen Behrens
- Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lynne D. Berry
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Clare Wilhelm
- Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dara Aisner
- Department of Pathology, University of Colorado, Denver, Colorado, USA
| | - Lynette Sholl
- Department of Pathology, Brigham and Women’s Hospital, Harvard University, Boston, Massachusetts, USA
| | - Bruce E. Johnson
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - David J. Kwiatkowski
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts, USA
| | - Ignacio I. Wistuba
- Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Paul A. Bunn
- Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, Colorado, USA
| | - John Minna
- Hamon Center for Therapeutic Oncology Research
- Departments of Internal Medicine and Pharmacology
- Simmons Comprehensive Cancer Center, and
| | - Guanghua Xiao
- Quantitative Biomedical Research Center, The Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Simmons Comprehensive Cancer Center, and
- Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Mark G. Kris
- Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Yang Xie
- Quantitative Biomedical Research Center, The Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Simmons Comprehensive Cancer Center, and
- Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA
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10
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Recent and Future Strategies to Overcome Resistance to Targeted Therapies and Immunotherapies in Metastatic Colorectal Cancer. J Clin Med 2022; 11:jcm11247523. [PMID: 36556139 PMCID: PMC9783354 DOI: 10.3390/jcm11247523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide, and 20% of patients with CRC present at diagnosis with metastases. The treatment of metastatic CRC is based on a fluoropyrimidine-based chemotherapy plus additional agents such as oxaliplatin and irinotecan. To date, on the basis of the molecular background, targeted therapies (e.g., monoclonal antibodies against epidermal growth factor receptor or inhibiting angiogenesis) are administered to improve the treatment of metastatic CRC. In addition, more recently, immunological agents emerged as effective in patients with a defective mismatch repair system. The administration of targeted therapies and immunotherapy lead to a significant increase in the survival of patients; however these drugs do not always prove effective. In most cases the lack of effectiveness is due to the development of primary resistance, either a resistance-inducing factor is already present before treatment or resistance is acquired when it occurs after treatment initiation. In this review we describe the most relevant targeted therapies and immunotherapies and expand on the reasons for resistance to the different approved or under development targeted drugs. Then we showed the possible mechanisms and drugs that may lead to overcoming the primary or acquired resistance in metastatic CRC.
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11
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Chan S, Zhang Y, Wang J, Yu Q, Peng X, Zou J, Zhou L, Tan L, Duan Y, Zhou Y, Hur H, Ai J, Wang Z, Ren X, Zhang Z, Ding K. Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors. J Med Chem 2022; 65:15374-15390. [PMID: 36358010 DOI: 10.1021/acs.jmedchem.2c01346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The receptor tyrosine kinase AXL is a promising target for anticancer drug discovery. Herein, we describe the discovery of 3-aminopyrazole derivatives as new potent and selective AXL kinase inhibitors. One of the representative compounds, 6li, potently inhibited AXL enzymatic activity with an IC50 value of 1.6 nM, and tightly bound with AXL protein with a Kd value of 0.26 nM, while was obviously less potent against most of the 403 wild-type kinases evaluated. Cell-based assays demonstrated that compound 6li potently inhibited AXL signaling, suppressed Ba/F3-TEL-AXL cell proliferation, reversed TGF-β1-induced epithelial-mesenchymal transition, and dose-dependently impeded cancer cell migration and invasion. Compound 6li also showed reasonable pharmacokinetic properties in rats and exhibited significant in vivo antitumor efficacy in a xenograft model of highly metastatic murine breast cancer 4T1 cells. Taken together, this study provides a new potent and selective AXL inhibitor for further anticancer drug discovery.
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Affiliation(s)
- Shingpan Chan
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Yunong Zhang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Jie Wang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Qiuchun Yu
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Xia Peng
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Jian Zou
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Licheng Zhou
- State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China
| | - Li Tan
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Yunxin Duan
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Yang Zhou
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si 16499, Gyeonggi-do, Republic of Korea
| | - Jing Ai
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Zhen Wang
- State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China
| | - Xiaomei Ren
- State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China
| | - Zhang Zhang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Ke Ding
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
- State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China
- The First Affiliated Hospital (Huaqiao Hospital), Jinan University, #601 Huangpu Avenue West, Guangzhou 510632, China
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12
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Alghamian Y, Soukkarieh C, Abbady AQ, Murad H. Investigation of role of CpG methylation in some epithelial mesenchymal transition gene in a chemoresistant ovarian cancer cell line. Sci Rep 2022; 12:7494. [PMID: 35523936 PMCID: PMC9076839 DOI: 10.1038/s41598-022-11634-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 04/20/2022] [Indexed: 11/24/2022] Open
Abstract
Ovarian cancer is one of the lethal gynecologic cancers. Chemoresistance is an essential reason for treatment failure and high mortality. Emerging evidence connects epithelial-mesenchymal transition (EMT) like changes and acquisition of chemoresistance in cancers. Including EMT, DNA methylation influences cellular processes. Here, EMT-like changes were investigated in cisplatin-resistant A2780 ovarian cancer cells (A2780cis), wherein role of DNA methylation in some EMT genes regulations was studied. Cell viability assay was carried out to test the sensitivity of A2780, and A2780cis human cancer cell lines to cisplatin. Differential mRNA expression of EMT markers using qPCR was conducted to investigate EMT like changes. CpG methylation role in gene expression regulation was investigated by 5-azacytidine (5-aza) treatment. DNA methylation changes in EMT genes were identified using Methylscreen assay between A2780 and A2780cis cells. In order to evaluate if DNA methylation changes are causally underlying EMT, treatment with 5-aza followed by Cisplatin was done on A2780cis cells. Accordingly, morphological changes were studied under the microscope, whereas EMT marker's gene expression changes were investigated using qPCR. In this respect, A2780cis cell line has maintained its cisplatin tolerance ability and exhibits phenotypic changes congruent with EMT. Methylscreen assay and qPCR study have revealed DNA hypermethylation in promoters of epithelial adhesion molecules CDH1 and EPCAM in A2780cis compared to the cisplatin-sensitive parental cells. These changes were concomitant with gene expression down-regulation. DNA hypomethylation associated with transcription up-regulation of the mesenchymal marker TWIST2 was observed in the resistant cells. Azacytidine treatment confirmed DNA methylation role in regulating gene expression of CDH1, EPCAM and TWIST2 genes. A2780cis cell line undergoes EMT like changes, and EMT genes are regulated by DNA methylation. To that end, a better understanding of the molecular alterations that correlate with chemoresistance may lead to therapeutic benefits such as chemosensitivity restoration.
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Affiliation(s)
- Yaman Alghamian
- Department of Animal Biology, Faculty of Sciences, Damascus University, Damascus, Syria
| | - Chadi Soukkarieh
- Department of Animal Biology, Faculty of Sciences, Damascus University, Damascus, Syria
| | - Abdul Qader Abbady
- Human Genetics Division, Department of Molecular Biology and Biotechnology, Atomic Energy Commission of Syria (AECS), P.O. Box 6091, Damascus, Syria
| | - Hossam Murad
- Human Genetics Division, Department of Molecular Biology and Biotechnology, Atomic Energy Commission of Syria (AECS), P.O. Box 6091, Damascus, Syria.
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13
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Nicoś M, Krawczyk P. Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer. Cancers (Basel) 2022; 14:1813. [PMID: 35406585 PMCID: PMC8998004 DOI: 10.3390/cancers14071813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022] Open
Abstract
Data indicate that many driver alterations from the primary tumor of non-small cell lung cancer (NSCLC) are predominantly shared across all metastases; however, disseminating cells may also acquire a new genetic landscape across their journey. By comparing the constituent subclonal mutations between pairs of primary and metastatic samples, it is possible to derive the ancestral relationships between tumor clones, rather than between tumor samples. Current treatment strategies mostly rely on the theory that metastases are genetically similar to the primary lesions from which they arise. However, intratumor heterogeneity (ITH) affects accurate diagnosis and treatment decisions and it is considered the main hallmark of anticancer therapy failure. Understanding the genetic changes that drive the metastatic process is critical for improving the treatment strategies of this deadly condition. Application of next generation sequencing (NGS) techniques has already created knowledge about tumorigenesis and cancer evolution; however, further NGS implementation may also allow to reconstruct phylogenetic clonal lineages and clonal expansion. In this review, we discuss how the clonality of genetic alterations influence the seeding of primary and metastatic lesions of NSCLC. We highlight that wide genetic analyses may reveal the phylogenetic trajectories of NSCLC evolution, and may pave the way to better management of follow-up and treatment.
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Affiliation(s)
- Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland;
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14
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Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal 2022; 20:27. [PMID: 35264191 PMCID: PMC8905758 DOI: 10.1186/s12964-022-00840-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the second most common and the leading cause of cancer related deaths globally. Tyrosine Kinase Inhibitors (TKIs) are among the common therapeutic strategies in lung cancer patients, however the treatment process fails in a wide range of patients due to TKIs resistance. Given that the use of anti-cancer drugs can always have side effects on normal tissues, predicting the TKI responses can provide an efficient therapeutic strategy. Therefore, it is required to clarify the molecular mechanisms of TKIs resistance in lung cancer patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological cellular processes. In the present review, we discussed the miRNAs that have been associated with TKIs responses in lung cancer. MiRNAs mainly exert their role on TKIs response through regulation of Tyrosine Kinase Receptors (TKRs) and down-stream signaling pathways. This review paves the way for introducing a panel of miRNAs for the prediction of TKIs responses in lung cancer patients.
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