Triple-negative breast cancer (TNBC) is among the most aggressive subtypes of the disease that does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Circular RNAs (circRNAs) are a type of non-coding RNA with a circular shape formed by non-standard splicing or reverse splicing. Numerous circRNAs exhibit abnormal expression in various malignancies, showing their critical role in the emergence and growth of tumors. Recent studies have shown evidence supporting the idea that certain circRNAs regulate the proliferation and metastasis of TNBC. In addition, circRNAs alter metabolism and the immune microenvironment to promote or inhibit the development of TNBC. Notably, circRNAs may affect the efficacy of clinical drug therapy, serve as therapeutic targets, and be used as molecular biomarkers in the future. Herein, we will first summarize the biogenesis and function of circRNAs. Then, we will explain current research on circRNAs related to TNBC and their potential to serve as therapeutic targets or biomarkers for future drug development, providing a new direction and idea for TNBC therapy.
{"title":"The therapeutic potential of circular RNA in triple-negative breast cancer","authors":"Aiqi Xu, Lewei Zhu, Chengcai Yao, Wen Zhou, Ziyun Guan","doi":"10.20517/cdr.2023.141","DOIUrl":"https://doi.org/10.20517/cdr.2023.141","url":null,"abstract":"Triple-negative breast cancer (TNBC) is among the most aggressive subtypes of the disease that does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Circular RNAs (circRNAs) are a type of non-coding RNA with a circular shape formed by non-standard splicing or reverse splicing. Numerous circRNAs exhibit abnormal expression in various malignancies, showing their critical role in the emergence and growth of tumors. Recent studies have shown evidence supporting the idea that certain circRNAs regulate the proliferation and metastasis of TNBC. In addition, circRNAs alter metabolism and the immune microenvironment to promote or inhibit the development of TNBC. Notably, circRNAs may affect the efficacy of clinical drug therapy, serve as therapeutic targets, and be used as molecular biomarkers in the future. Herein, we will first summarize the biogenesis and function of circRNAs. Then, we will explain current research on circRNAs related to TNBC and their potential to serve as therapeutic targets or biomarkers for future drug development, providing a new direction and idea for TNBC therapy.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"32 37","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140671864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leonie de Wilt, B. Sobocki, Gerrit Jansen, Hessan Tabeian, Steven de Jong, G. J. Peters, F. Kruyt
Aim: The therapeutic targeting of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors in cancer, including non-small cell lung cancer (NSCLC), is a widely studied approach for tumor selective apoptotic cell death therapy. However, apoptosis resistance is often encountered. The main aim of this study was to investigate the apoptotic mechanism underlying TRAIL sensitivity in three bortezomib (BTZ)-resistant NSCLC variants, combining induction of both the intrinsic and extrinsic pathways. Methods: Sensitivity to TRAIL in BTZ-resistant variants was determined using a tetrazolium (MTT) and a clonogenic assay. A RT-qPCR profiling mRNA array was used to determine apoptosis pathway-specific gene expression. The expression of these proteins was determined through ELISA assays and western Blotting, while apoptosis (sub-G1) and cytokine expression were determined using flow cytometry. Apoptotic genes were silenced by specific siRNAs. Lipid rafts were isolated with fractional ultracentrifugation. Results: A549BTZR (BTZ-resistant) cells were sensitive to TRAIL in contrast to parental A549 cells, which are resistant to TRAIL. TRAIL-sensitive H460 cells remained equally sensitive for TRAIL as H460BTZR. In A549BTZR cells, we identified an increased mRNA expression of TNFRSF11B [osteoprotegerin (OPG)] and caspase-1, -4 and -5 mRNAs involved in cytokine activation and immunogenic cell death. Although the OPG, interleukin-6 (IL-6), and interleukin-8 (IL-8) protein levels were markedly enhanced (122-, 103-, and 11-fold, respectively) in the A549BTZR cells, this was not sufficient to trigger TRAIL-induced apoptosis in the parental A549 cells. Regarding the extrinsic apoptotic pathway, the A549BTZR cells showed TRAIL-R1-dependent TRAIL sensitivity. The shift of TRAIL-R1 from non-lipid into lipid rafts enhanced TRAIL-induced apoptosis. In the intrinsic apoptotic pathway, a strong increase in the mRNA and protein levels of the anti-apoptotic myeloid leukemia cell differentiation protein (Mcl-1) and B-cell leukemia/lymphoma 2 (Bcl-2) was found, whereas the B-cell lymphoma-extra large (Bcl-xL) expression was reduced. However, the stable overexpression of Bcl-xL in the A549BTZR cells did not reverse the TRAIL sensitivity in the A549BTZR cells, but silencing of the BH3 Interacting Domain Death Agonist (BID) protein demonstrated the importance of the intrinsic apoptotic pathway, regardless of Bcl-xL. Conclusion: In summary, increased sensitivity to TRAIL-R1 seems predominantly related to the relocalization into lipid rafts and increased extrinsic and intrinsic apoptotic pathways.
{"title":"Mechanisms underlying reversed TRAIL sensitivity in acquired bortezomib-resistant non-small cell lung cancer cells","authors":"Leonie de Wilt, B. Sobocki, Gerrit Jansen, Hessan Tabeian, Steven de Jong, G. J. Peters, F. Kruyt","doi":"10.20517/cdr.2024.14","DOIUrl":"https://doi.org/10.20517/cdr.2024.14","url":null,"abstract":"Aim: The therapeutic targeting of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors in cancer, including non-small cell lung cancer (NSCLC), is a widely studied approach for tumor selective apoptotic cell death therapy. However, apoptosis resistance is often encountered. The main aim of this study was to investigate the apoptotic mechanism underlying TRAIL sensitivity in three bortezomib (BTZ)-resistant NSCLC variants, combining induction of both the intrinsic and extrinsic pathways.\u0000 Methods: Sensitivity to TRAIL in BTZ-resistant variants was determined using a tetrazolium (MTT) and a clonogenic assay. A RT-qPCR profiling mRNA array was used to determine apoptosis pathway-specific gene expression. The expression of these proteins was determined through ELISA assays and western Blotting, while apoptosis (sub-G1) and cytokine expression were determined using flow cytometry. Apoptotic genes were silenced by specific siRNAs. Lipid rafts were isolated with fractional ultracentrifugation.\u0000 Results: A549BTZR (BTZ-resistant) cells were sensitive to TRAIL in contrast to parental A549 cells, which are resistant to TRAIL. TRAIL-sensitive H460 cells remained equally sensitive for TRAIL as H460BTZR. In A549BTZR cells, we identified an increased mRNA expression of TNFRSF11B [osteoprotegerin (OPG)] and caspase-1, -4 and -5 mRNAs involved in cytokine activation and immunogenic cell death. Although the OPG, interleukin-6 (IL-6), and interleukin-8 (IL-8) protein levels were markedly enhanced (122-, 103-, and 11-fold, respectively) in the A549BTZR cells, this was not sufficient to trigger TRAIL-induced apoptosis in the parental A549 cells. Regarding the extrinsic apoptotic pathway, the A549BTZR cells showed TRAIL-R1-dependent TRAIL sensitivity. The shift of TRAIL-R1 from non-lipid into lipid rafts enhanced TRAIL-induced apoptosis. In the intrinsic apoptotic pathway, a strong increase in the mRNA and protein levels of the anti-apoptotic myeloid leukemia cell differentiation protein (Mcl-1) and B-cell leukemia/lymphoma 2 (Bcl-2) was found, whereas the B-cell lymphoma-extra large (Bcl-xL) expression was reduced. However, the stable overexpression of Bcl-xL in the A549BTZR cells did not reverse the TRAIL sensitivity in the A549BTZR cells, but silencing of the BH3 Interacting Domain Death Agonist (BID) protein demonstrated the importance of the intrinsic apoptotic pathway, regardless of Bcl-xL.\u0000 Conclusion: In summary, increased sensitivity to TRAIL-R1 seems predominantly related to the relocalization into lipid rafts and increased extrinsic and intrinsic apoptotic pathways.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"46 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140721614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Spiliopoulou, Paramjit Kaur, Tracey Hammett, Giusy Di Conza, M. Lahn
Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory (Treg) cells (CD4+CD25+FOXP3+). The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on Treg cells demonstrates that such intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory (Teff/Treg) ratio. While clinical development with large molecules has shown the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of Treg cells. This review will summarize the lessons currently applied to develop novel clinical agents that target Treg cells.
原发性或继发性（即获得性）抗药性是癌症患者的常见病，通常与T调节（Treg）细胞（CD4+CD25+FOXP3+）数量过高有关。伊匹单抗（ipilimumab）的获批以及以 Treg 细胞上的细胞表面蛋白为靶点的类似药剂的开发表明，这种干预措施可以克服癌症患者的抗药性。因此，细胞毒性 T 淋巴细胞抗原-4（CTLA-4）靶向药物的临床开发和随后的批准可以作为类似药物的原型。这类新药希望具有高度特异性，并降低毒性，同时提高效应 T 细胞功能或效应 T/T 调节（Teff/Treg）比率。虽然大分子药物的临床开发取得了最大进展，但针对免疫调节的小分子抑制剂也越来越多地进入早期临床研究。这些新的小分子抑制剂通常针对特定的细胞内信号通路[如磷酸肌醇-3-激酶δ（PI3K-δ）]，这些通路在调节 Treg 细胞的功能方面发挥着重要作用。本综述将总结目前用于开发针对 Treg 细胞的新型临床药物的经验教训。
{"title":"Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers","authors":"P. Spiliopoulou, Paramjit Kaur, Tracey Hammett, Giusy Di Conza, M. Lahn","doi":"10.20517/cdr.2023.46","DOIUrl":"https://doi.org/10.20517/cdr.2023.46","url":null,"abstract":"Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory (Treg) cells (CD4+CD25+FOXP3+). The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on Treg cells demonstrates that such intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory (Teff/Treg) ratio. While clinical development with large molecules has shown the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of Treg cells. This review will summarize the lessons currently applied to develop novel clinical agents that target Treg cells.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":" 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139624815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Angiogenesis by endothelial cells (ECs) is essential for tumor growth. Angiogenesis inhibitors are used in combination with anticancer drugs in many tumor types, but tumors eventually become resistant. Previously, the underlying mechanism for developing drug resistance was considered to be a change in the characteristics of tumor cells whereas ECs were thought to be genetically stable and do not contribute to drug resistance. However, tumor endothelial cells (TECs) have been shown to differ from normal endothelial cells (NECs) in that they exhibit chromosomal abnormalities, angiogenic potential, and drug resistance. Extracellular vesicles (EVs) secreted by tumor cells have recently attracted attention as a factor involved in the acquisition of such abnormalities. Various cells communicate with each other through EVs, and it has been reported that tumor-derived EVs act on other tumor cells or stromal cells to develop drug resistance. Drug-resistant tumor cells confer drug resistance to recipient cells by transporting mRNAs encoding ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily C member 1 (ABCC1) as well as miRNAs involved in signaling such as Akt, drug efflux transporters, and P-glycoprotein modulators via EVs. However, there are limited reports on the acquisition of drug resistance in ECs by tumor-derived EVs. Since drug resistance of ECs may induce tumor metastasis and support tumor cell proliferation, the mechanism underlying the development of resistance should be elucidated to find therapeutic application. This review provides insight into the acquisition of drug resistance in ECs via tumor EVs in the tumor microenvironment.
{"title":"Acquisition of drug resistance in endothelial cells by tumor-derived extracellular vesicles and cancer progression","authors":"Masahiro Morimoto, N. Maishi, K. Hida","doi":"10.20517/cdr.2023.121","DOIUrl":"https://doi.org/10.20517/cdr.2023.121","url":null,"abstract":"Angiogenesis by endothelial cells (ECs) is essential for tumor growth. Angiogenesis inhibitors are used in combination with anticancer drugs in many tumor types, but tumors eventually become resistant. Previously, the underlying mechanism for developing drug resistance was considered to be a change in the characteristics of tumor cells whereas ECs were thought to be genetically stable and do not contribute to drug resistance. However, tumor endothelial cells (TECs) have been shown to differ from normal endothelial cells (NECs) in that they exhibit chromosomal abnormalities, angiogenic potential, and drug resistance. Extracellular vesicles (EVs) secreted by tumor cells have recently attracted attention as a factor involved in the acquisition of such abnormalities. Various cells communicate with each other through EVs, and it has been reported that tumor-derived EVs act on other tumor cells or stromal cells to develop drug resistance. Drug-resistant tumor cells confer drug resistance to recipient cells by transporting mRNAs encoding ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily C member 1 (ABCC1) as well as miRNAs involved in signaling such as Akt, drug efflux transporters, and P-glycoprotein modulators via EVs. However, there are limited reports on the acquisition of drug resistance in ECs by tumor-derived EVs. Since drug resistance of ECs may induce tumor metastasis and support tumor cell proliferation, the mechanism underlying the development of resistance should be elucidated to find therapeutic application. This review provides insight into the acquisition of drug resistance in ECs via tumor EVs in the tumor microenvironment.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"1 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patrick L. Sweeney, Yash Suri, A. Basu, V. Koshkin, A. Desai
Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.
{"title":"Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma","authors":"Patrick L. Sweeney, Yash Suri, A. Basu, V. Koshkin, A. Desai","doi":"10.20517/cdr.2023.89","DOIUrl":"https://doi.org/10.20517/cdr.2023.89","url":null,"abstract":"Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"49 50","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139151033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Multiple myeloma (MM) is a type of hematological cancer that occurs when B cells become malignant. Various drugs such as proteasome inhibitors, immunomodulators, and compounds that cause DNA damage can be used in the treatment of MM. Autophagy, a type 2 cell death mechanism, plays a crucial role in determining the fate of B cells, either promoting their survival or inducing cell death. Therefore, autophagy can either facilitate the progression or hinder the treatment of MM disease. In this review, autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response (UPR), bone marrow microenvironment (BMME), drug resistance, hypoxia, DNA repair and transcriptional regulation, and apoptosis. The genes that are effective in each mechanism and research efforts on this subject were discussed in detail. Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered. The efficacy of drugs that regulate autophagy in MM was examined, and clinical trials on this subject were included. Consequently, among the autophagy mechanisms that are effective in MM, the most suitable ones to be used in the treatment were expressed. The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized. Ultimately, this review aims to provide a comprehensive overview of MM disease, encompassing autophagy mechanisms, drugs, clinical studies, and further studies.
多发性骨髓瘤（MM）是一种由 B 细胞恶变而成的血液肿瘤。蛋白酶体抑制剂、免疫调节剂和导致DNA损伤的化合物等多种药物可用于治疗多发性骨髓瘤。自噬是一种第二类细胞死亡机制，在决定 B 细胞的命运方面起着至关重要的作用，它可以促进 B 细胞的存活，也可以诱导细胞死亡。因此，自噬既可以促进 MM 疾病的进展，也可以阻碍 MM 疾病的治疗。本综述从未折叠蛋白反应（UPR）、骨髓微环境（BMME）、耐药性、缺氧、DNA 修复和转录调控以及细胞凋亡等方面，对可能对 MM 细胞有效的自噬机制进行了阐述和评估。会议详细讨论了每种机制中的有效基因以及这方面的研究工作。会议还讨论了新药靶向的信号通路，以便在 MM 疾病中从自噬中获益。研究了调节自噬的药物在 MM 中的疗效，并纳入了这方面的临床试验。因此，在对 MM 有效的自噬机制中，最适合用于治疗的机制得到了表述。三维模型和微流控系统对于发现自噬新药和个性化治疗的重要性得到了强调。最后，本综述旨在全面概述 MM 疾病，包括自噬机制、药物、临床研究和进一步研究。
{"title":"Autophagy-related mechanisms for treatment of multiple myeloma","authors":"Gül Kozalak, Ali Koşar","doi":"10.20517/cdr.2023.108","DOIUrl":"https://doi.org/10.20517/cdr.2023.108","url":null,"abstract":"Multiple myeloma (MM) is a type of hematological cancer that occurs when B cells become malignant. Various drugs such as proteasome inhibitors, immunomodulators, and compounds that cause DNA damage can be used in the treatment of MM. Autophagy, a type 2 cell death mechanism, plays a crucial role in determining the fate of B cells, either promoting their survival or inducing cell death. Therefore, autophagy can either facilitate the progression or hinder the treatment of MM disease. In this review, autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response (UPR), bone marrow microenvironment (BMME), drug resistance, hypoxia, DNA repair and transcriptional regulation, and apoptosis. The genes that are effective in each mechanism and research efforts on this subject were discussed in detail. Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered. The efficacy of drugs that regulate autophagy in MM was examined, and clinical trials on this subject were included. Consequently, among the autophagy mechanisms that are effective in MM, the most suitable ones to be used in the treatment were expressed. The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized. Ultimately, this review aims to provide a comprehensive overview of MM disease, encompassing autophagy mechanisms, drugs, clinical studies, and further studies.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139159168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic lymphocytic leukemia (CLL) is common amongst leukemic malignancies, prompting dedicated investigation throughout the years. Over the last decade, the treatment for CLL has significantly advanced with agents targeting B-cell lymphoma 2 (BCL2), Bruton’s tyrosine kinase, and CD20. Single agents or combinations of these targets have proven efficacy. Unfortunately, resistance to one or multiple of the new treatment targets develops. Our review investigates various mechanisms of resistance to BCL2 inhibitors, including mutations in BCL2, alterations in the Bcl protein pathway, epigenetic modifications, genetic heterogeneity, Richter transformation, and alterations in oxidative phosphorylation. Additionally, the review will discuss potential avenues to overcome this resistance with novel agents such as bispecific antibodies, Bruton’s tyrosine kinase (BTK) degraders, non-covalent BTK inhibitors, and chimeric antigen receptor T (CART).
{"title":"Targeting BCL2 pathways in CLL: a story of resistance and ingenuity","authors":"Amanda Reyes, Tanya Siddiqi","doi":"10.20517/cdr.2023.97","DOIUrl":"https://doi.org/10.20517/cdr.2023.97","url":null,"abstract":"Chronic lymphocytic leukemia (CLL) is common amongst leukemic malignancies, prompting dedicated investigation throughout the years. Over the last decade, the treatment for CLL has significantly advanced with agents targeting B-cell lymphoma 2 (BCL2), Bruton’s tyrosine kinase, and CD20. Single agents or combinations of these targets have proven efficacy. Unfortunately, resistance to one or multiple of the new treatment targets develops. Our review investigates various mechanisms of resistance to BCL2 inhibitors, including mutations in BCL2, alterations in the Bcl protein pathway, epigenetic modifications, genetic heterogeneity, Richter transformation, and alterations in oxidative phosphorylation. Additionally, the review will discuss potential avenues to overcome this resistance with novel agents such as bispecific antibodies, Bruton’s tyrosine kinase (BTK) degraders, non-covalent BTK inhibitors, and chimeric antigen receptor T (CART).","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139230263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Drug resistance that affects patients universally is a major challenge in cancer therapy. The development of drug resistance in cancer cells is a multifactor event, and its process involves numerous mechanisms that allow these cells to evade the effect of treatments. As a result, the need to understand the molecular mechanisms underlying cancer drug sensitivity is imperative. Traditional 2D cell culture systems have been utilized to study drug resistance, but they often fail to mimic the 3D milieu and the architecture of real tissues and cell-cell interactions. As a result of this, 3D cell culture systems are now considered a comprehensive model to study drug resistance in vitro . Cancer cells exhibit an in vivo behavior when grown in a three-dimensional environment and react to therapy more physiologically. In this review, we discuss the relevance of main 3D culture systems in the study of potential approaches to overcome drug resistance and in the identification of personalized drug targets with the aim of developing patient-specific treatment strategies that can be put in place when resistance emerges.
{"title":"Emerging roles of 3D-culture systems in tackling tumor drug resistance","authors":"Amin Nikdouz, Francesca Orso","doi":"10.20517/cdr.2023.93","DOIUrl":"https://doi.org/10.20517/cdr.2023.93","url":null,"abstract":"Drug resistance that affects patients universally is a major challenge in cancer therapy. The development of drug resistance in cancer cells is a multifactor event, and its process involves numerous mechanisms that allow these cells to evade the effect of treatments. As a result, the need to understand the molecular mechanisms underlying cancer drug sensitivity is imperative. Traditional 2D cell culture systems have been utilized to study drug resistance, but they often fail to mimic the 3D milieu and the architecture of real tissues and cell-cell interactions. As a result of this, 3D cell culture systems are now considered a comprehensive model to study drug resistance in vitro . Cancer cells exhibit an in vivo behavior when grown in a three-dimensional environment and react to therapy more physiologically. In this review, we discuss the relevance of main 3D culture systems in the study of potential approaches to overcome drug resistance and in the identification of personalized drug targets with the aim of developing patient-specific treatment strategies that can be put in place when resistance emerges.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139253681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The use of immune checkpoint inhibitors (ICIs) has increased exponentially in the past decade, although its progress specifically for breast cancer has been modest. The first U.S. Food and Drug Administration approval for ICI in breast cancer came in 2019, eight years after the first-ever approval of an ICI. At present, current indications for ICIs are relevant only to a subset of patients with triple-negative breast cancer, or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway. With an increasing understanding of the limitations of using ICIs, which stem from breast cancer being innately poorly immunogenic, as well as the presence of various intrinsic and acquired resistance pathways, ongoing trials are evaluating different combination therapies to overcome these barriers. In this review, we aim to describe the development timeline of ICIs and resistance mechanisms limiting their utility, and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.
{"title":"Immune checkpoint inhibitors in breast cancer: development, mechanisms of resistance and potential management strategies","authors":"Rachel SJ Wong, Rebecca JM Ong, Joline SJ Lim","doi":"10.20517/cdr.2023.58","DOIUrl":"https://doi.org/10.20517/cdr.2023.58","url":null,"abstract":"The use of immune checkpoint inhibitors (ICIs) has increased exponentially in the past decade, although its progress specifically for breast cancer has been modest. The first U.S. Food and Drug Administration approval for ICI in breast cancer came in 2019, eight years after the first-ever approval of an ICI. At present, current indications for ICIs are relevant only to a subset of patients with triple-negative breast cancer, or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway. With an increasing understanding of the limitations of using ICIs, which stem from breast cancer being innately poorly immunogenic, as well as the presence of various intrinsic and acquired resistance pathways, ongoing trials are evaluating different combination therapies to overcome these barriers. In this review, we aim to describe the development timeline of ICIs and resistance mechanisms limiting their utility, and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"168 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139264371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Victoria A. Remley, Joel Linden, Todd W. Bauer, Julien Dimastromatteo
Tumors survive by creating a tumor microenvironment (TME) that suppresses antitumor immunity. The TME suppresses the immune system by limiting antigen presentation, inhibiting lymphocyte and natural killer (NK) cell activation, and facilitating T cell exhaustion. Checkpoint inhibitors like anti-PD-1 and anti-CTLA are immunostimulatory antibodies, and their blockade extends the survival of some but not all cancer patients. Extracellular adenosine triphosphate (ATP) is abundant in inflamed tumors, and its metabolite, adenosine (ADO), is a driver of immunosuppression mediated by adenosine A2A receptors (A2AR) and adenosine A2B receptors (A2BR) found on tumor-associated lymphoid and myeloid cells. This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.
{"title":"Unlocking antitumor immunity with adenosine receptor blockers","authors":"Victoria A. Remley, Joel Linden, Todd W. Bauer, Julien Dimastromatteo","doi":"10.20517/cdr.2023.63","DOIUrl":"https://doi.org/10.20517/cdr.2023.63","url":null,"abstract":"Tumors survive by creating a tumor microenvironment (TME) that suppresses antitumor immunity. The TME suppresses the immune system by limiting antigen presentation, inhibiting lymphocyte and natural killer (NK) cell activation, and facilitating T cell exhaustion. Checkpoint inhibitors like anti-PD-1 and anti-CTLA are immunostimulatory antibodies, and their blockade extends the survival of some but not all cancer patients. Extracellular adenosine triphosphate (ATP) is abundant in inflamed tumors, and its metabolite, adenosine (ADO), is a driver of immunosuppression mediated by adenosine A2A receptors (A2AR) and adenosine A2B receptors (A2BR) found on tumor-associated lymphoid and myeloid cells. This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.","PeriodicalId":9538,"journal":{"name":"Cancer drug resistance","volume":"44 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135405803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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