Dysregulated mitochondrial dynamics in cancer: Unlocking new strategies to combat drug resistance.

The expression of HNF1 homeobox B (HNF1B) is associated with cancer risk in several tumors, including ovarian cancer, and its decreased expression play roles in cancer development. However, the study of HNF1B and cancer is limited, and its association with drug resistance in cancer has never been reported. On the basis of array data retrieved from Oncomine and Gene Expression Omnibus(GEO) online database, we found that the mRNA expression of HNF1B in 586ovarian serous cystadenocarcinomas and in platinum-resistant A2780 epithelial ovarian cancer cells was significantly decreased, indicating a potential role of HNF1B in drug resistance in ovarian cancer. Based on this finding, comprehensive bioinformatics analyses, including protein/gene interaction, protein-small molecule/chemical interaction, biological process annotation, gene co-occurrence and pathway enrichment analysis and microRNA-mRNA interaction, were performed to illustrate the association of HNF1B with drug resistance in ovarian cancer. We found that among the proteins/genes, small molecules/chemicals and microRNAs which directly interacted with HNF1B, the majority was associated with drug resistance in cancer, particularly in ovarian cancer. Biological process annotation revealed that HNF1B closely related to 24 biological processes which were all notably associated with ovarian cancer and drug resistance. These results indicated that the downregulation of HNF1B may contribute to drug resistance in ovarian cancer, via its direct interactions with these drug resistance-related proteins/genes, small molecules/chemicals and microRNAs, and via its regulations on the drug resistance-related biological processes. Pathway enrichment analysis of 36 genes which co-occurred with HNF1B, ovarian cancer and drug resistance indicated that the HNF1B may perform its drug resistance-related functions through 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling. Collectively, in this study, we illustrated for the first time that HNF1B may contribute to drug resistance in ovarian cancer, potentially through the 4 pathways. The present study may pave the way for further investigation of the drug resistance-related functions of HNF1B in ovarian cancer.

The rapid spread of drug resistance in bacteria as well as cancer has developed into a significant threat to the global public health. According to the World Health Organization (WHO), antibiotic resistance is present in every country, and various national and international health organizations, including the United Nations and the Infectious Diseases Society of America have called for the urgent development of new treatment and diagnostic strategies. The Centers for Disease Control and Prevention reports approximately 10 million deaths worldwide each year in connection with antibiotic resistance. Similarly, drug resistance in cancer is believed to be responsible for treatment failure in up to 90% of metastatic cancer patients. Cellular resistance mechanisms in both bacteria and cancer include cell membrane protein modifications, intracellular drug target alterations, and the over expression of efflux pumps. The latter are the result of an over-expression of efflux pump proteins, which enable cells to expel drugs rapidly from the cell interior, before these compounds can take effective action. Drug compounds and efflux pump proteins have recently caught the attention by the electrochemical community to develop new methodologies to understand and detect drug resistance in both bacteria and cancer by electrochemistry. Our research efforts focus specifically on drug compounds expelled from living biological cells by electrochemistry and their detection by standard electrochemical techniques, such as volatmmetry, as well as specialized instrumentation, such as scanning electrochemical microscopy (SECM). This presentation covers the characterization of common drug compounds, but also newly investigational antibiotic hybrids. Recent advances are presented towards the quantification of drug resistance in epithelial ovarian cancer (EOC), which has the highest mortality rate among gynecological cancers.

The intricate relationship between inflammation and cancer progression has been well-documented, with chronic inflammation playing a pivotal role in tumor development and drug resistance. This project investigates how cancer-intrinsic inflammation influences drug response, aiming to identify key regulators that could serve as therapeutic targets to overcome drug resistance in colorectal cancer (CRC). We hypothesize that distinct inflammation types within cancer cells modulate their response to chemotherapy, potentially driving resistance. Our study is structured around two specific aims: First, we investigate the inflammation-type-dependent drug response using single-cell barcoded colon cancer cells. Our preliminary studies demonstrated that CRC cells in an inflamed microenvironment, particularly those with STING pathway activation, exhibit distinct responses to 5-FU treatment compared to non-inflamed cells. This finding underscores the need to consider inflammation as a critical factor in cancer treatment strategies. By characterizing the response of inflamed and non-inflamed cells to various drug treatments at single-cell resolution, we aim to identify the specific inflammation-driven mechanisms that contribute to drug resistance. Second, we focus on the characterization and validation of key regulators identified in inflamed CRC cells. We will validate candidate genes through functional assays, including gene knockdown experiments, to uncover the molecular pathways through which inflammation modulates drug response. By linking the distinct inflammatory states within cancer cells to drug resistance, we aim to identify novel biomarkers and therapeutic targets that could enhance the effectiveness of existing treatments. Our research has the potential to significantly impact the treatment of CRC by providing a deeper understanding of how inflammation drives drug resistance, ultimately guiding the development of more effective, personalized therapies for patients with inflamed tumors. This approach addresses the urgent need for targeted strategies to overcome the challenges posed by inflammation-associated drug resistance in cancer therapy. Citation Format: Kerem Fidan, Semih Can Akincilar, Tim Stuart, Vinay Tergaonkar. Deciphering Inflammation-Driven Drug Resistance Mechanisms in Colorectal Cancer through Single-Cell Barcoding [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P71.

NEKs [NIMA (never in mitosis gene A)-related expressed kinase] are involved in ovarian cancer development and progression, while their association with drug resistance is limited, especially NEK11, and its relationship with drug resistance has never been reported. In this study, on the basis of comprehensive bioinformatic analyses, including mRNA expression according to microarray data, protein/gene interaction, protein-small molecule interaction, annotation of biological process and microRNA-mRNA interaction analysis, we revealed that the NEK11 mRNA was significantly downregulated in 586 cases of ovarian serous cystadenocarcinomas and cisplatin-resistant A2780 ovarian cancer cells, and interacted with 22 proteins and 4 small molecules which all were contributed to drug resistance in ovarian cancer. Furthermore, seven cell cycle-related biological processes were annotated with NEK11, drug resistance and ovarian cancer, suggesting that NEK11 potentially was involved in the drug resistance in ovarian cancer via its regulatory roles in the cell cycle. In addition, among the eight microRNAs predicted to be most strongly targeting NEK11, the majority were involved in drug resistance in ovarian and other cancers. All those results provide a very strong possibility that the notable downregulation of NEK11 in cisplatin-resistant ovarian cancer cells was involved in drug resistance, via its interactions with drug resistance-related genes, proteins, small molecules, microRNAs and biological processes, particularly the cell cycle-related processes. To our knowledge, this is the first report of the association of NEK11 with drug resistance in cancer, and it would pave the way for further investigation of the drug resistance-related functions of this gene.

Drug resistance in cancer cells significantly diminishes treatment efficacy, leading to recurrence and metastasis. A critical factor contributing to this resistance is the epigenetic alteration of gene expression via RNA modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing. These modifications are pivotal in regulating RNA splicing, translation, transport, degradation, and stability. Governed by “writers,” “readers,” and “erasers,” RNA modifications impact numerous biological processes and cancer progression, including cell proliferation, stemness, autophagy, invasion, and apoptosis. Aberrant RNA modifications can lead to drug resistance and adverse outcomes in various cancers. Thus, targeting RNA modification regulators offers a promising strategy for overcoming drug resistance and enhancing treatment efficacy. This review consolidates recent research on the role of prevalent RNA modifications in cancer drug resistance, with a focus on m6A, m1A, m5C, m7G, Ψ, and A-to-I editing. Additionally, it examines the regulatory mechanisms of RNA modifications linked to drug resistance in cancer and underscores the existing limitations in this field.

Editorial: Signalling pathways in anti-cancer drug resistance.

Introduction: Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies.Areas covered: Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer and potential strategies to overcome this.Expert opinion: Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers.

Drug resistance in ovarian cancer: from the laboratory to the clinic

Mitochondrial signaling pathways and their role in cancer drug resistance

Ovarian cancer is usually diagnosed in the advanced stages when the cancer has metastasised making it one of the most common gynaecological cancers with a high mortality rate. The development of drug resistance in such cancers is unfavourable. The aim of this study was to produce biomarkers of drug resistance in ovarian cancer, which can be used to identify a drug-resistant phenotype in patients allowing for alternative treatments besides the first-line choices of carboplatin and paclitaxel. Various methods were used in the study from western blotting to analyse protein expression, epithelial antigen staining to assess epithelial state of cell, scratch assays to determine drug-resistant phenotype, MTT assays to assess drug-inhibitor responses, Annexin V-FITC apoptosis detection assay for cell viability assessment, gene silencing assays to assess drug sensitivity on gene silencing and qPCR array led approach to identify genes upregulated in drug-resistant cell lines. Using an EMT-led approach, analysis of five common EMT markers led to the determination of SLUG as a probable biomarker with E-CADHERIN and β-CATENIN as possible biomarkers. Examination of the downstream signalling proteins of the MET receptor revealed RAC1 could be another possible biomarker. Using the qPCR-led approach, a list of upregulated genes in drug-resistant cell lines was produced with further protein analyses revealing ZEB1, STAT3 and WNT proteins as possible biomarkers. As EMT was used as a starting point to identify markers of drug resistance, to determine its association with drug resistance, a drug-resistant cell line model was produced through the induction of EMT. In conclusion, this study has produced a list of possible biomarkers of drug resistance in ovarian cancer fulfilling its aims. Further investigation of the biomarkers beyond the use of cell models could determine their reliability as biomarkers of drug resistance in ovarian cancer in the clinical setting.

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

The metabolic profiles of breast cancer cells are different from normal mammary epithelial cells. Breast cancer cells that gain resistance to therapeutic interventions can reprogram their endogenous metabolism in order to adapt and proliferate despite high oxidative stress and hypoxic conditions. Drug resistance in breast cancer, regardless of subgroups, is a major clinical setback. Although recent advances in genomics and proteomics research has given us a glimpse into the heterogeneity that exists even within subgroups, the ability to precisely predict a tumor’s response to therapy remains elusive. Metabolomics as a quantitative, high through put technology offers promise towards devising new strategies to establish predictive, diagnostic and prognostic markers of breast cancer. Along with other “omics” technologies that include genomics, transcriptomics, and proteomics, metabolomics fits into the puzzle of a comprehensive systems biology approach to understand drug resistance in breast cancer. In this review, we highlight the challenges facing successful therapeutic treatment of breast cancer and the innovative approaches that metabolomics offers to better understand drug resistance in cancer.

Drug resistance in cancer is a major obstacle to successful chemotherapy. Cancer cells exposed to antitumour drugs may be directly induced to express a subset of genes that could confer resistance, thus allowing a population of cells to survive and form the relapsed resistant tumour. Alternatively, some cancer cells may be expressing an array of genes that could confer intrinsic resistance, and exposure to cytotoxic drugs select for the survival of these cells that form the relapsed tumour. To assess whether there are differences in the mechanism of drug resistance by induction or selection, we used complementary DNA (cDNA) microarray to monitor mRNA expression in breast cancer cells that were either transiently treated with or selected for resistance to doxorubicin. Expression profiles of the human breast carcinoma MCF-7 cells transiently treated with doxorubicin were compared with those obtained from a MCF-7 cell line selected for resistance to doxorubicin. Transient treatment with doxorubicin altered the expression of a diverse group of genes in a time-dependent manner. We found a subset of transiently induced genes constitutively overexpressed in cells selected for resistance to doxorubicin, suggesting that cancer cells activate a distinct set of genes in acquiring drug resistance by either induction or selection. Our studies demonstrate the feasibility of obtaining molecular profiles of drug resistance in cancer cells by cDNA microarray, which might yield insights into the mechanisms of resistance during chemotherapy, and suggest alternative methods of treatment.

Development of drug resistance in cancer is one of the main challenges in chemotherapy, and many mechanisms are still unknown. In this study, we show that tumor necrosis factor alpha (TNFalpha) increases postdrug survival from 5-fluoro-2'-deoxyuridine (FdUrd) in two human colon tumor cell lines. This resulted in the development of drug-resistant cells in a TNFalpha-dependent manner. Interestingly, although the drug-resistant cells were selected using FdUrd, they are also resistant to a number of other antimetabolites in the DNA synthesis pathway in a TNFalpha-dependent manner. Only in the drug-resistant cells (p35-colo201) TNFalpha treatment resulted in G(0)-G(1) arrest but not in the parental colo201 and other cell types. Blocking TNFalpha-induced cell cycle arrest sensitized drug-resistant cells to FdUrd. TNFalpha-induced cell cycle arrest required IKK. IKK inhibition by a small molecule inhibitor or by the knockdown of IKKalpha, IKKbeta, or RelA/p65 using siRNA, but not the inhibition of JNK, MEK, p38, or caspase-8 pathways, blocked TNFalpha-induced G(0)-G(1) arrest and restored sensitivity to FdUrd of drug-resistant cells. TNFalpha reduced the transcripts and protein levels of phosphorylated retinoblastoma protein (Rb), Rb, E2F1, and Cdk4 only in drug-resistant p35-colo201 cells. This effect of TNFalpha was reversed by IKK inhibitor, suggesting that TNFalpha-induced cell cycle arrest is probably due to the reduction of Rb, E2F1, and Cdk4. Taken together, this study shows that, in vitro, TNFalpha-induced cell cycle arrest through IKK can provide a mechanism for the development of drug resistance to anti-cancer drugs, purine and pyrimidine analogues.

This Review delves into the mechanisms behind drug resistance in colorectal cancer (CRC), particularly examining the role of nutrient depletion and its contribution to multidrug resistance (MDR). The study highlights metabolic adaptations of cancer cells as well as metabolic adaptations of cancer cells under low nutrient availability, including shifts in glycolysis and lipid metabolism. It emphasizes the significance of MDR1 and its encoded efflux transporter, P-glycoprotein (P-gp/B1), in mediating drug resistance and how pathways such as HIF1α, AKT, and mTOR influence the expression of P-gp/B1 under limited nutrient availability. Additionally, the Review explores the dual roles of autophagy in drug sensitivity and resistance under nutrient limited conditions. It further investigates the involvement of lysosomes and mitochondria, focusing on their roles in drug sequestration and the challenges posed by lysosomal entrapment facilitated by non-enzymatic processes and ABC transporters like P-gp/B1. Finally, the Review underscores the importance of understanding the interplay between drug sequestration, lysosomal functions, nutrient depletion, and MDR1 gene modulation. It suggests innovative strategies, including structural modifications and nanotechnology, as promising approaches to overcoming drug resistance in cancer therapy.