Molecular aspects of cancer cell resistance to chemotherapy
TL;DR: The stemness properties of a few cancer cells as well as components of the tumor stroma, like fibroblasts and tumor-associated macrophages but also hypoxia, also help tumor to resist to anticancer agents.
About: This article is published in Biochemical Pharmacology.The article was published on 2013-05-01. It has received 341 citations till now. The article focuses on the topics: Cancer stem cell & Cancer.
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Journal Article•
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore
PL02-05
All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.
2,737 citations
Journal Article•
TL;DR: It is reported that PTEN activation contributes to trastuzumab's antitumor activity and PTEN deficiency is a powerful predictor for trastzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.
Abstract: 2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.
1,574 citations
TL;DR: This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance with the advanced design and alternative mechanisms of drug delivery known for different nanodrugs.
581 citations
Cites background from "Molecular aspects of cancer cell re..."
...Cell cycle arrest does not occur when mutations, chromosomal rearrangements, and epigenetic changes are present, even when induced by anticancer therapies that induce DNA damage to cause cytotoxicity [30]....
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TL;DR: A novel mechanism of lncRNA-regulated autophagy-related chemoresistance in GC is revealed, casting new lights on the understanding ofChemoresistance.
Abstract: Chemoresistance has long been recognized as a major obstacle in cancer therapy. Clarifying the underlying mechanism of chemoresistance would result in novel strategies to improve patient’s response to chemotherapeutics. lncRNA expression levels in gastric cancer (GC) cells was detected by quantitative real-time PCR (qPCR). MALAT1 shRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate MALAT1 expression. In vitro and in vivo assays were performed to investigate the functional role of MALAT1 in autophagy associated chemoresistance. We showed that chemoresistant GC cells had higher levels of MALAT1 and increased autophagy compared with parental cells. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 promoted autophagy in gastric cancer cells. Knockdown of MALAT1 sensitized GC cells to chemotherapeutics. MALAT1 acts as a competing endogenous RNA for miR-23b-3p and attenuates the inhibitory effect of miR-23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. Taken together, our study revealed a novel mechanism of lncRNA-regulated autophagy-related chemoresistance in GC, casting new lights on the understanding of chemoresistance.
247 citations
Cites background from "Molecular aspects of cancer cell re..."
...Previous studies have revealed that both intrinsic and acquired chemoresistance come from the genetic and epigenetic modifications occurring in cancer cells [5]....
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...Although great efforts have been taken into clarifying the molecular mechanisms of the chemoresistance [5], the precise mechanisms remain largely unknown....
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TL;DR: Investigation into the factors triggering the observed doxorubicin resistance revealed that cell-to-ECM interactions played a pivotal role and correlated with the up-regulation of pro-survival proteins in 3D ECM-containing cell culture conditions following exposure to doxorbicin.
Abstract: Cancer cell resistance to therapeutics can result from acquired or de novo-mediated factors. Here, we have utilised advanced breast cancer cell culture models to elucidate de novo doxorubicin resistance mechanisms. The response of breast cancer cell lines (MCF-7 and MDA-MB-231) to doxorubicin was examined in an in vitro three-dimensional (3D) cell culture model. Cells were cultured with Matrigel™ enabling cellular arrangements into a 3D architecture in conjunction with cell-to-extracellular matrix (ECM) contact. Breast cancer cells cultured in a 3D ECM-based model demonstrated altered sensitivity to doxorubicin, when compared to those grown in corresponding two-dimensional (2D) monolayer culture conditions. Investigations into the factors triggering the observed doxorubicin resistance revealed that cell-to-ECM interactions played a pivotal role. This finding correlated with the up-regulation of pro-survival proteins in 3D ECM-containing cell culture conditions following exposure to doxorubicin. Inhibition of integrin signalling in combination with doxorubicin significantly reduced breast cancer cell viability. Furthermore, breast cancer cells grown in a 3D ECM-based model demonstrated a significantly reduced proliferation rate in comparison to cells cultured in 2D conditions. Collectively, these novel findings reveal resistance mechanisms which may contribute to reduced doxorubicin sensitivity.
224 citations
Cites background from "Molecular aspects of cancer cell re..."
...Resistance mechanisms specific to topoisomerase II inhibitors have been identified and include enhanced levels of efflux and alterations to the expression of the topoisomerase II [6]....
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References
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TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
51,099 citations
TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
Abstract: Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
8,063 citations
TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
7,056 citations
"Molecular aspects of cancer cell re..." refers background in this paper
...factor receptors as well as mutation/overexpression of signal transduction proteins lead to sustained proliferative signaling and aberrant proliferation [8]....
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TL;DR: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development.
Abstract: Background Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. Methods To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Results Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Conclusions Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)
6,672 citations
TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Abstract: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
6,417 citations
"Molecular aspects of cancer cell re..." refers background in this paper
...expression and sequencing data completed with data of their drugsensitive profiles to more than twenty different anticancer drugs [98]....
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