{"pmid":"35956408","gene":"ABCG2","doi":"10.3390/nu14153232","title":"Selenium Yeast and Fish Oil Combination Diminishes Cancer Stem Cell Traits and Reverses Cisplatin Resistance in A549 Sphere Cells.","abstract":"Cisplatin is a prevalent chemotherapeutic agent used for non-small cell lung cancer (NSCLC) that is difficult to treat by targeted therapy, but the emergence of resistance severely limits its efficacy. Thus, an effective strategy to combat cisplatin resistance is required. This study demonstrated that, at clinically achievable concentrations, the combination of selenium yeast (Se-Y) and fish oil (FO) could synergistically induce the apoptosis of cancer stem cell (CSC)-like A549 NSCLC sphere cells, accompanied by a reversal of their resistance to cisplatin. Compared to parental A549 cells, sphere cells have higher cisplatin resistance and possess elevated CSC markers (CD133 and ABCG2), epithelial-mesenchymal transition markers (anexelekto (AXL), vimentin, and N-cadherin), and cytoprotective endoplasmic reticulum (ER) stress marker (glucose-regulated protein 78) and increased oncogenic drivers, such as yes-associated protein, transcriptional coactivator with PDZ-binding motif, β-catenin, and cyclooxygenase-2. In contrast, the proapoptotic ER stress marker CCAAT/enhancer-binding protein homologous protein and AMP-activated protein kinase (AMPK) activity were reduced in sphere cells. The Se-Y and FO combination synergistically counteracted the above molecular features of A549 sphere cells and diminished their elevated CSC-like side population. AMPK inhibition by compound C restored the side population proportion diminished by this nutrient combination. The results suggest that the Se-Y and FO combination can potentially improve the outcome of cisplatin-treated NSCLC with phenotypes such as A549 cells.","year":"2022","keywords":"AMPK; cancer stem cell; cisplatin; fish oil; lung cancer; selenium; side population; A549 Cells; AMP-Activated Protein Kinases; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Fish Oils; Humans; Lung Neoplasms; Neoplastic Stem Cells; Phenotype; Saccharomyces cerevisiae; Selenium","pubmed_count":13}
{"pmid":"35427871","gene":"ABCG2","doi":"10.1016/j.drup.2022.100832","title":"Clinical implications of germline variations for treatment outcome and drug resistance for small molecule kinase inhibitors in patients with non-small cell lung cancer.","abstract":"Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.","year":"2022","keywords":"NSCLC; Outcome; Pharmacogenetics; Pharmacokinetics; SNP; Single nucleotide polymorphisms; Small molecule kinase inhibitors; Toxicity; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance; Gefitinib; Germ Cells; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Treatment Outcome","pubmed_count":13}
{"pmid":"34255797","gene":"ABCG2","doi":"10.1371/journal.pone.0253852","title":"Metabolomic and transcriptomic analysis reveals endogenous substrates and metabolic adaptation in rats lacking Abcg2 and Abcb1a transporters.","abstract":"Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.","year":"2021","keywords":"ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Brain; Gene Expression Profiling; Gene Knockout Techniques; Histidine; Kidney; Liver; Male; Metabolic Clearance Rate; Metabolomics; Purines; Pyrimidines; Rats; Rats, Transgenic","pubmed_count":13}
{"pmid":"34065402","gene":"ABCG2","doi":"10.3390/ijms22105384","title":"KRAS and EGFR Mutations Differentially Alter ABC Drug Transporter Expression in Cisplatin-Resistant Non-Small Cell Lung Cancer.","abstract":"Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment.","year":"2021","keywords":"ABC drug transporters; AC; EGFR; KRAS; NSCLC; WNT signalling; A549 Cells; ATP-Binding Cassette Transporters; Aged; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Line, Tumor; Cisplatin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Proto-Oncogene Proteins p21(ras); Tumor Microenvironment","pubmed_count":13}
{"pmid":"33455278","gene":"ABCG2","doi":"10.1021/acsbiomaterials.0c00887","title":"SOX2Mediates Carbon Nanotube-Induced Fibrogenesis and Fibroblast Stem Cell Acquisition.","abstract":"Certain nanosized particles like carbon nanotubes (CNTs) are known to induce pulmonary fibrosis, but the underlying mechanisms are unclear, and efforts to prevent this disease are lacking. Fibroblast-associated stem cells (FSCs) have been suggested as a critical driver of fibrosis induced by CNTs by serving as a renewable source of extracellular matrix-producing cells; however, a detailed understanding of this process remains obscure. Here, we demonstrated that single-walled CNTs induced FSC acquisition and fibrogenic responses in primary human lung fibroblasts. This was indicated by increased expression of stem cell markers (e.g., CD44 and ABCG2) and fibrogenic markers (e.g., collagen and &#x3b1;-SMA) in CNT-exposed cells. These cells also showed increased sphere formation, anoikis resistance, and aldehyde dehydrogenase (ALDH) activities, which are characteristics of stem cells. Mechanistic studies revealed sex-determining region Y-box 2 (SOX2), a self-renewal associated transcription factor, as a key driver of FSC acquisition and fibrogenesis. Upregulation and colocalization of SOX2 and COL1 were found in the fibrotic lung tissues of CNT-exposed mice via oropharyngeal aspiration after 56 days. The knockdown of SOX2 by gene silencing abrogated the fibrogenic and FSC-inducing effects of CNTs. Chromatin immunoprecipitation assays identified SOX2-binding sites on <i>COL1A1<\/i> and <i>COL1A2<\/i>, indicating SOX2 as a transcription factor in collagen synthesis. SOX2 was also found to play a critical role in TGF-&#x3b2;-induced fibrogenesis through its collagen- and FSC-inducing effects. Since many nanomaterials are known to induce TGF-&#x3b2;, our findings that SOX2 regulate FSCs and fibrogenesis may have broad implications on the fibrogenic mechanisms and treatment strategies of various nanomaterial-induced fibrotic disorders.","year":"2021","keywords":"fibrogenicity; myofibroblasts; nanomaterial; self-renewal; Animals; Fibroblasts; Lung; Mice; Nanotubes, Carbon; Pulmonary Fibrosis; Stem Cells","pubmed_count":13}
{"pmid":"32560222","gene":"ABCG2","doi":"10.3390/cancers12061590","title":"Preclinical Evaluation of the Novel Small-Molecule MSI-N1014 for Treating Drug-Resistant Colon Cancer via the LGR5/&#x3b2;-catenin/miR-142-3p Network and Reducing Cancer-Associated Fibroblast Transformation.","abstract":"Colorectal cancer represents one of the most prevalent malignancies globally, with an estimated 140,000 new cases in the United States alone in 2019. Despite advancements in interventions, drug resistance occurs in virtually all patients diagnosed with late stages of colon cancer. Amplified epidermal growth factor receptor (EGFR) signaling is one of the most prevalent oncogenic drivers in patients and induces increased Janus kinase (JAK)/signal transduction and activator of transcription (STAT) and &#x3b2;-catenin functions, all of which facilitate disease progression. Equally important, cancer-associated fibroblasts (CAFs) transformed by cancer cells within the tumor microenvironment (TME) further facilitate malignancy by secreting interleukin (IL)-6 and augmenting STAT3 signaling in colon cancer cells and promoting the generation of cancer stem-like cells (CSCs). Based on these premises, single-targeted therapeutics have proven ineffective for treating malignant colon cancer, and alternative multiple-targeting agents should be explored. Herein, we synthesized a tetracyclic heterocyclic azathioxanthone, MSI-N1014, and demonstrated its therapeutic potential both in vitro and in vivo. First, we used a co-culture system to demonstrate that colon cancer cells co-cultured with CAFs resulted in heightened 5-fluorouracil (5-FU) resistance and tumor sphere-forming ability and increased side populations, accompanied by elevated expression of cluster of differentiation 44 (CD44), &#x3b2;-catenin, leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), and ATP-binding cassette super-family G member 2 (ABCG2). MSI-N1014 suppressed cell viability, colony formation, and migration in both DLD1 and HCT116 cells. MSI-N1014 treatment led to decreased expressions of oncogenic markers, including mammalian target of rapamycin (mTOR), EGFR, and IL-6 and stemness markers such as CD44, &#x3b2;-catenin, and LGR5. More importantly, MSI-N1014 treatment suppressed the transformation of CAFs, and was associated with decreased secretion of IL-6 and vascular endothelial growth factor (VEGF) by CAFs. Furthermore, MSI-N1014 treatment resulted in significantly reduced oncogenic properties, namely the migratory ability, tumor-sphere generation, and resistance against 5-FU. Notably, an increased level of the tumor suppressor, miR-142-3p, whose targets include LGR5, IL-6, and ABCG2, was detected in association with MSI-N1014 treatment. Finally, we demonstrated the therapeutic potential of MSI-N1014 in vivo<i>,<\/i> where combined treatment with MSI-N1014 and 5-FU led to the lowest tumor growth, followed by MSI-N1014 only, 5-FU, and the vehicle control. Tumor samples from the MSI-N1014 group showed markedly reduced expressions of LGR5, &#x3b2;-catenin, IL-6, and mTOR, but increased expression of the tumor suppressor, miR-142-3p, according to qRT-PCR analysis. Collectively, we present preclinical support for the application of MSI-N1014 in treating 5-FU-resistant colon cancer cells. Further investigation is warranted to translate these findings into clinical settings.","year":"2020","keywords":"cancer stemness; cancer-associated fibroblasts (CAFs); colon cancer; drug resistance; miR-142; small-molecule therapeutics","pubmed_count":13}
{"pmid":"30115694","gene":"ABCG2","doi":"10.1158/0008-5472.CAN-18-0757","title":"Transcriptomics and Transposon Mutagenesis Identify Multiple Mechanisms of Resistance to the FGFR Inhibitor AZD4547.","abstract":"In human cancers, FGFR signaling is frequently hyperactivated by deregulation of FGF ligands or by activating mutations in the FGFR receptors such as gene amplifications, point mutations, and gene fusions. As such, FGFR inhibitors are considered an attractive therapeutic strategy for patients with mutations in FGFR family members. We previously identified <i>Fgfr2<\/i> as a key driver of invasive lobular carcinoma (ILC) in an <i>in vivo<\/i> insertional mutagenesis screen using the <i>Sleeping Beauty<\/i> transposon system. Here we explore whether these FGFR-driven ILCs are sensitive to the FGFR inhibitor AZD4547 and use transposon mutagenesis in these tumors to identify potential mechanisms of resistance to therapy. Combined with RNA sequencing-based analyses of AZD4547-resistant tumors, our <i>in vivo<\/i> approach identified several known and novel potential resistance mechanisms to FGFR inhibition, most of which converged on reactivation of the canonical MAPK-ERK signaling cascade. Observed resistance mechanisms included mutations in the tyrosine kinase domain of FGFR2, overexpression of MET, inactivation of RASA1, and activation of the drug-efflux transporter ABCG2. ABCG2 and RASA1 were identified only from <i>de novo<\/i> transposon insertions acquired during AZD4547 treatment, demonstrating that insertional mutagenesis in mice is an effective tool for identifying potential mechanisms of resistance to targeted cancer therapies.<b>Significance:<\/b> These findings demonstrate that a combined approach of transcriptomics and insertional mutagenesis <i>in vivo<\/i> is an effective method for identifying potential targets to overcome resistance to therapy in the clinic. <i>Cancer Res; 78(19); 5668-79. &#xa9;2018 AACR<\/i>.","year":"2019","keywords":"ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Benzamides; Carcinoma, Lobular; Cell Line, Tumor; DNA Transposable Elements; Drug Resistance, Neoplasm; Female; Gene Amplification; Humans; MAP Kinase Signaling System; Mice; Mutagenesis; Mutation; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasm Transplantation; Piperazines; Pyrazoles; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 2; Sequence Analysis, RNA; Transcriptome; p120 GTPase Activating Protein","pubmed_count":13}
{"pmid":"28340578","gene":"ABCG2","doi":"10.1186/s12931-017-0537-6","title":"ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling.","abstract":"Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno- (AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in-depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n&#x2009;=&#x2009;90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune-fluorescent staining and transport function analysis. Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity. The difference in the Wnt microenvironment in AC and SCC leads to variations in ABC transporter expression. Cisplatin via induction of canonical Wnt signaling up-regulates ABCB1 and ABCG2 drug transporters that are not transporters for cisplatin itself but are transporters for drugs that are frequently used in combination therapy with cisplatin modulating drug response.","year":"2017","keywords":"ABC transporters; Cisplatin; Lung cancer; Wnt signaling; A549 Cells; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cisplatin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Proteins; Treatment Outcome; Tumor Cells, Cultured; Wnt Signaling Pathway","pubmed_count":13}
{"pmid":"27785389","gene":"ABCG2","doi":"10.4172/2168-9431.1000150","title":"Gene Expression in Single Cells Isolated from the CWR-R1 Prostate Cancer Cell Line and Human Prostate Tissue Based on the Side Population Phenotype.","abstract":"Defining biological signals at the single cell level can identify cancer initiating driver mutations. Techniques to isolate single cells such as microfluidics sorting and magnetic capturing systems have limitations such as: high cost, labor intense, and the requirement of a large number of cells. Therefore, the goal of our current study is to identify a cost and labor effective, reliable, and reproducible technique that allows single cell isolation for analysis to promote regular laboratory use, including standard reverse transcription PCR (RT-PCR). In the current study, we utilized single prostate cells isolated from the CWR-R1 prostate cancer cell line and human prostate clinical specimens, based on the ATP binding cassette (ABC) transporter efflux of dye cycle violet (DCV), side population assay. Expression of four genes: ABCG2; Aldehyde dehydrogenase1A1 (ALDH1A1); androgen receptor (AR); and embryonic stem cell marker, Oct-4, were determined. Results from the current study in the CWR-R1 cell line showed ABCG2 and ALDH1A1 gene expression in 67% of single side population cells and in 17% or 100% of non-side population cells respectively. Studies using single cells isolated from clinical specimens showed that the Oct-4 gene is detected in only 22% of single side population cells and in 78% of single non-side population cells. Whereas, AR gene expression is in 100% single side population and non-side population cells isolated from the same human prostate clinical specimen. These studies show that performing RT-PCR on single cells isolated by FACS can be successfully conducted to determine gene expression in single cells from cell lines and enzymatically digested tissue. While these studies provide a simple yes/no expression readout, the more sensitive quantitative RT-PCR would be able to provide even more information if necessary.","year":"2020","keywords":"ABCG2; Aldehyde dehydrogenase; Androgen receptor; Human prostate clinical specimens; Side population assay; Single cells","pubmed_count":13}
{"pmid":"27456282","gene":"ABCG2","doi":"10.1038/srep25956","title":"ABCG2 regulates self-renewal and stem cell marker expression but not tumorigenicity or radiation resistance of glioma cells.","abstract":"Glioma cells with stem cell traits are thought to be responsible for tumor maintenance and therapeutic failure. Such cells can be enriched based on their inherent drug efflux capability mediated by the ABC transporter ABCG2 using the side population assay, and their characteristics include increased self-renewal, high stem cell marker expression and high tumorigenic capacity in vivo. Here, we show that ABCG2 can actively drive expression of stem cell markers and self-renewal in glioma cells. Stem cell markers and self-renewal was enriched in cells with high ABCG2 activity, and could be specifically inhibited by pharmacological and genetic ABCG2 inhibition. Importantly, despite regulating these key characteristics of stem-like tumor cells, ABCG2 activity did not affect radiation resistance or tumorigenicity in vivo. ABCG2 effects were Notch-independent and mediated by diverse mechanisms including the transcription factor Mef. Our data demonstrate that characteristics of tumor stem cells are separable, and highlight ABCG2 as a potential driver of glioma stemness.","year":"2018","keywords":"ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Biomarkers, Tumor; Brain Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Neoplasm Proteins; Neoplasm Transplantation; Neoplastic Stem Cells; Radiation Tolerance; Receptors, Notch; Signal Transduction; Up-Regulation","pubmed_count":13}
{"pmid":"26318424","gene":"ABCG2","doi":"10.18632/oncotarget.4824","title":"Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of the androgen receptor.","abstract":"A systematic analysis of the genes involved in taxol resistance (txr) has never been performed. In the present study, we created txr ovarian carcinoma cell lines to identify the genes involved in chemoresistance. Transcriptome analysis revealed 1,194 overexpressed genes in txr cells. Among the upregulated genes, more than 12 cryptic transcription factors were identified using MetaCore analysis (including AR, C/EBP&#x3b2;, ER&#x3b1;, HNF4&#x3b1;, c-Jun/AP-1, c-Myc, and SP-1). Notably, individual silencing of these transcription factors (except HNF4`)sensitized txr cells to taxol. The androgen receptor (AR) and its target genes were selected for further analysis. Silencing AR using RNA interference produced a 3-fold sensitization to taxol in txr cells, a response similar to that produced by silencing abcb1. AR silencing also downregulated the expression of prominent txr gene candidates (including abcb1, abcb6, abcg2, bmp5, fat3, fgfr2, h1f0, srcrb4d, and tmprss15). In contrast, AR activation using the agonist DHT upregulated expression of the target genes. Individually silencing seven out of nine (78%) AR-regulated txr genes sensitized txr cells to taxol. Inhibition of AKT and JNK cellular kinases using chemical inhibitors caused a dramatic suppression of AR expression. These results indicate that the AR represents a critical driver of gene expression involved in txr.","year":"2016","keywords":"androgen receptor; multiple drug resistance; ovarian cancer; taxol; transcription factor; Antineoplastic Agents, Phytogenic; Carcinoma; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Inhibitory Concentration 50; Male; Oligonucleotide Array Sequence Analysis; Oligonucleotides; Ovarian Neoplasms; Paclitaxel; Phenotype; Polymerase Chain Reaction; Prostatic Neoplasms; RNA Interference; Receptors, Androgen; Transcription Factors; Transcriptome; Up-Regulation","pubmed_count":13}
{"pmid":"25982012","gene":"ABCG2","doi":"10.1016/j.lungcan.2015.04.004","title":"Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases.","abstract":"In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.","year":"2016","keywords":"Brain metastases; Everolimus; Exceptional responder; Lung cancer; Next generation sequencing; RET; Vandetanib; mTOR; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Everolimus; Female; Gene Amplification; Gene Rearrangement; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Neuroimaging; Oncogene Proteins, Fusion; Piperidines; Proto-Oncogene Proteins c-akt; Quinazolines","pubmed_count":13}
{"pmid":"24634705","gene":"ABCG2","doi":"10.6000/1929-2279.2013.02.04.5","title":"Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma.","abstract":"Lung cancer is the most commonly diagnosed cancer in the world. \"Driver\" and \"passenger\" mutations identified in lung cancer indicate that genetics play a major role in the development of the disease, progression, metastasis and response to therapy. Survival rates for lung cancer treatment have remained stagnant at ~15% over the past 40 years in patients with disseminated disease despite advances in surgical techniques, radiotherapy and chemotherapy. Resistance to therapy; either intrinsic or acquired has been a major hindrance to treatment leading to great interest in studies seeking to understand and overcome resistance. Genetic information gained from molecular analyses has been critical in identifying druggable targets and tumor profiles that may be predictors of therapeutic response and mediators of resistance. Mutated or overexpressed epidermal growth factor receptor (EGFR) and translocations in the echinoderm microtubule-associated protein-like 4 (<i>EML4<\/i>)-anaplastic lymphoma kinase (<i>ALK<\/i>) genes (EML4-ALK) are examples of genetic aberrations resulting in targeted therapies for both localized and metastatic disease. Positive clinical responses have been noted in patients harboring these genetic mutations when treated with targeted therapies compared to patients lacking these mutations. Resistance is nonetheless a major factor contributing to the failure of targeted agents and standard cytotoxic agents. In this review, we examine molecular mechanisms that are potential drivers of resistance in non-small cell lung carcinoma, the most frequently diagnosed form of lung cancer. The mechanisms addressed include resistance to molecular targeted therapies as well as conventional chemotherapeutics through the activity of multidrug resistance proteins.","year":"2022","keywords":"ABC transporters; ABCB1; ABCC1; ABCC10; ABCG2; EGFR; EML4-ALK; Non-small cell lung cancer; drug resistance; tyrosine kinase inhibitors","pubmed_count":13}