Genetic heterogeneity and cancer drug resistance nicholas c turner, jorge s reisfilho despite the success of targeted therapies in the treatment of cancer, the development of resistance limits the ability to translate this method into a curative treatment. Drug resistance and combating drug resistance in cancer. Resistance to anticancer drugs can be acquired by several mechanisms within neoplastic cells, defined as 1 alteration of drug. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Overviews and methods contains chapters that cover topics such as. Resistance to chemotherapeutic agents can involve various intrinsic cellular processes including drug efflux, increased resistance to apoptosis, increased dna damage repair capabilities in response to platinum salts or other dnadamaging drugs, drug inactivation, drug target. Experimental approaches that can help predict the eventual clinical drug resistance, coupled with the evolution of systematic genomic. Pdf cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of. Compared with various controls, the lead conjugate exhibits cancerselective activation, restores. Control of multidrug resistance gene mdr1 and cancer. The geneticnongenetic duality of drug resistance in cancer.
The journal focuses on pharmacological aspects of drug resistance and its reversal, including drug design, drug delivery, drug distribution and cellular drug resistance, etc. All successful cancer therapies are limited by the development of drug resistance. In figure 1, a schematic overview of potential resistance mechanisms is given. Mar, 20 in addition, cancer is characterized by extensive genetic and epigenetic alterations 2,3 and mutations in drug targets may also be responsible for increased drug resistance 4. Multidrug resistance of cancer cells is a potentially surmountable obstacle to effective chemotherapy of cancer. An evolving paradigm resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. We have discussed examples of drug resistance reported for both cancer cells and infectious diseases. Micrornas mirnas are small noncoding rnas with a length of about 1925 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. The role of deubiquitinating enzymes in cancer drug resistance. This is a very serious problem that may lead to recurrence of disease or even death. Furthermore, at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and combination. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin.
Cancer drug resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal. Mathematical modeling and computational prediction of. Cancer, acquired drug resistance, cancer cell lines, drug adaptation, cancer therapy, cancer models introduction. Definition of drug resistance nci dictionary of cancer.
Atpbinding cassette abc transporters, including mdr1 abcb1, mrp1 abcc1 and. Drug resistance is a wellknown phenomenon that results when diseases become tolerant to pharmaceutical treatments. Crossresistance is the phenomenon where a patient is being treated with one drug, and where the tumor acquires a type of drug resistance that enables it to avoid being killed by. The current strategy centers around a conjugate that triggers a reprogramming of the mitochondrial metabolism.
Download fulltext pdf download fulltext pdf download fulltext pdf. Drug resistance is a common cause of treatment failure in cancer. Information of drug sensitivity and mutations in drug targets will be helpful for developing prediction models for predicting mutations responsible for drug resistance in cancer. For example, dna changes or other genetic changes may change the way the drug gets into the cancer cells or the way the drug is broken down. Experimental approaches that can help predict the eventual clinical drug resistance, coupled with the evolution of systematic genomic and.
Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This concept was first considered when bacteria became resistant to certain antibiotics, but since then similar mechanisms have been found to occur in other diseases, including cancer. Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic cancerous cells, or the ability of cancer cells to survive and grow despite anticancer therapies. Download cancer drug resistance cancer drug discovery.
Investigating biliary duct cancer mutations with lipika. The role of autophagy and apoptosis in the drug resistance of cancer. Use of combinations of cancer drugs, sequential therapy, adaptive therapy and topical ablation of. Cell adhesion molecules on stromal cells and extracellular. Cancer, acquired drug resistance, cancer cell lines, drug adaptation, cancer therapy, cancer models introduction despite improvements in therapy outcomes in recent decades, except for a few exceptions e. This section is intended to introduce some of the main ways in which cancer cells can resist treatments. To promote academic exchange and knowledge sharing, oae provides an outstanding academic platform for biomedical experts and scholars all over the world. Various mechanisms that have been proposed include enhanced intracellular concentration of the drug by endocytosis, 1 inhibition of multidrug. Lipika goyals educational and personal background and why she chose the path that she did. Download the ebook cancer drug resistance cancer drug discovery and development in pdf or epub format and read it directly on your mobile phone, computer or any device. Surgery remains one of the leading therapeutic interventions for treating solid tumours, and controlling infection during surgery can mean the difference between life and death. Many anticancer drugs require metabolic activation, and thus cancer cells can develop resistance through decreased drug activation. Lori hazlehurst, miles hacker, in pharmacology, 2009. More than 30 years ago, they discovered that in some cases, when patients go from being sensitive to resistant to treatment, their cancer cells start to overexpress abc transporters, he said.
Proteolysis targeting chimeras protacs as a novel and powerful strategy have attracted a great deal of attention both from academia and from industry for their sensitivity to drugresistant targets relying on their unique characteristics compared to those of. Can a new research institute usher in a new era of cancer management. The role and mechanisms of action of micrornas in cancer drug. Protacs as potential therapeutic agents for cancer drug. Resistance to treatment with anticancer drugs results from a variety of factors. Addressing drug resistance in cancer with macromolecular. Both clinical and experimental aspects of drug resistance in cancer are included. Key words cancer, multidrug resistance, abc transporters, drug transport, chemotherapy abstract the design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. There are myriad ways in which both populations of cells develop drug resistance depending upon the drug type and the cell type.
Mechanisms of acquired tumor drug resistance sciencedirect. Cancer drug resistancepublished on january 2009 report summarydrug resistance is the single most important cause of cancer treatment failure and carries a massive burden to patients, healthcareproviders, drug developers and society. Circumventing cancer drug resistance in the era of. May 16, 2019 can a new research institute usher in a new era of cancer management. More than 30 years ago, they discovered that in some cases, when patients go from being sensitive to resistant to treatment, their cancer cells start to. Overcoming drug resistance in cancer chemotherapy by using nms as delivery systems is a very hot area of research in this century. The macromolecular chemotherapeutic agents readily selfassemble into welldefined nanoparticles and show excellent activity in vitro against multiple cancer cell lines. On the other hand, cyp1a1 and cyp1a2 metabolize procarcinogens into carcinogenic forms in the liver, and most anticancer drugs are metabolized by this method. Mar 12, 2018 with cancer drug resistance, we aim to establish a forum for papers dealing with all aspects of drug resistance. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis andor treatment of cancer resistance to chemotherapy. A major cause of drug resistance from the tumor microenvironment is the ecm physical barrier. This volume discusses the latest advancements and technologies used in cancer drug resistance research. With cancer drug resistance, we aim to establish a forum for papers dealing with all aspects of drug resistance.
Drugadapted cancer cell lines as preclinical models of. Nigel hawkes investigates cancer will be conquered only by outwitting its ability to evolve more rapidly than the drugs treating it, the institute of cancer research has decided. Mathematical modeling and computational prediction of cancer. New study raises red flags about strategy to block cancer. In addition, cancer is characterized by extensive genetic and epigenetic alterations 2,3 and mutations in drug targets may also be responsible for increased drug resistance 4. Jci adipocyte and lipid metabolism in cancer drug resistance. Cancer drug resistance has become the major problem facing current clinical treatment via different kinds of therapies. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. Many studies on mechanisms of drug resistance rely on the use of cell cultures and animal models.
Furthermore, we describe how bacterialmediated cancer therapy, a bygone mode of treatment, has been. Cancer treatment and antimicrobial resistance the lancet. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. However, the mechanisms involved remain poorly understood. Download cancer drug resistance cancer drug discovery and. Unfortunately, novel drug development by cell and molecular biologists, often neglects the pharmacology of a drug. It is the reduction in effectiveness of a drug in curing a disease or condition. Drug combinations to overcome treatment resistance national. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Drug resistance in cancer is a wellknown phenomenon that results when cancer becomes tolerant to pharmaceutical treatment. To circumvent resistance issues, we have designed a new class of macromolecules as selfcontained chemotherapeutic agents. In recent decades, targeted therapy has become one of the standard strategies for treating malignant tumors, as targeted therapy can significantly improve the survival rate of cancer patients.
Secondary fgfr2 mutations drive drug resistance in bile. Peters and others published cancer drug resistance. Resistance to anti cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as 1 alteration of. The resistance against drugs in cancer patients stems from multiple factors, which constitute genetic heterogeneity like gene mutations, tumor microenvironment, exosomes, mirnas, high rate of drug efflux from cells, and so on. Drug resistance in cancer is the foremost threat in the present therapeutic era. While cancer cells dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug. Novel drug may be the answer in battling resistance in. Overcoming the challenges of cancer drug resistance through. Drug resistance is a serious impediment to the treatment of cancer. Hence, we argue that drug adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.
Secondary fgfr2 mutations drive drug resistance to fgfr inhibitors in bile duct cancer. Drug resistance to chemotherapeutics is a recurrent issue plaguing many cancer treatment regimens. The design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. This results in delayed prodrug activation and allows drug efflux mechanisms to be evaded.
On the other hand, cyp1a1 and cyp1a2 metabolize procarcinogens into carcinogenic forms in the liver, and most. Drug resistance may be present before treatment is given or may occur during or after treatment with the drug. Drug resistance is a wellknown phenomenon leading to a reduction in the effectiveness of pharmaceutical treatments. It also describes the epigenetic modifications that can induce drug resistance and considers how such. It has launched a new programme to tackle what its chief executive, paul workman, calls the biggest challenge in cancer biologycontrolling.
Many patients who experience breast cancer relapse struggle. Aim of cancerdr is to maintain pharmacological profiling data of anti cancer drugs, which will facilitate researchers to understand the effect of mutations in drug. While it is widely held that the phenomenon is genetic in nature, emerging evidence suggests that nongenetic mechanisms may also be important. Cancer drug resistance is an important cause of the often inevitable failure of targeted drug therapeutics in clinical anticancer treatment. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, dna damage repair, cell death inhibition. Resistance to anticancer drugs results from a variety of factors, such as individual genetic factors, and various cellular molecular targets. The role and mechanisms of action of micrornas in cancer.
In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance there are two general causes of antineoplastic therapy failure. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanisms of drug resistance. In cancer treatment, there are many things that may cause resistance to anticancer drugs. The problem of drug resistance in cancer has strong similarities to the field of infectious disease, in that both disciplines are challenged by highly proliferating. Clinically, drug resistance may develop either prior to drug therapy, or due to drug therapy. The anticancer activity of a drug can be limited by reduced drug influx or. Drug combinations to overcome treatment resistance.
Aguilar, in nanomaterials for medical applications, 20. Secondary fgfr2 mutations drive drug resistance to fgfr. Resistance to anticancer drugs arises from a wide variety of factors, such as. One of the impediments faced by patients with breast cancer is treatment or drug resistance. Drug resistance in cancer cells kapil mehta springer. Cancer drug resistance overviews and methods jose rueff. To establish whether sirt1 could be associated with development of drug resistance in cancer, we used various drugsensitive and drugresistant cancer cell lines representing neuroblastoma, osteosarcoma, mammary, and ovarian cancinomas 9. Cancer therapies are limited by the development of drug resistance, and mutations in drug targets is one of the main reasons for developing acquired resistance. Authoritative and insightful, cancer drug resistance offers basic and clinical investigators a stateoftheart synthesis of the many faceted research now available on the biology and genetics of tumor resistance, as well as exciting new approaches to its prevention and eradication. Definition drug resistance is the ability of microbes, such as bacteria, viruses, parasites, or fungi, to grow in the presence of a chemical drug that would normally kill it or limit its growth. Find industry reports, company profilesreportlinker and market statistics get this report now by email. Drug resistance in cancer an overview sciencedirect topics. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer.
New estrogen receptor found to be key player in tamoxifen resistance. Drug resistance and the resulting ineffectiveness of the drug treatment are responsible for up to 90% of the cancer related deaths37. The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Multidrug resistance mediated by mdrabc transporters. Antimicrobial resistance is of particular concern to cancer patients because the ability to prevent and cure infections is a cornerstone of cancer therapy.
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