Cancer chemotherapy resistance mdr is the innate andor acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The main obstacle to improve the clinical outcome of most of the therapeutic modalities discussed in the previous chapter is therapy resistance, either intrinsic or acquired after treatment. The evolution and ecology of resistance in cancer therapy. Beyond this clear progress, new challenges emerge now on. A major objective of this book is to reveal unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive and prognostic biomarkers to enable patient stratification and tailor treatments. Translational value of mouse models in oncology drug development. Wed like to understand how you use our websites in order to improve them. Mechanisms of drug resistance in cancer therapy springer. School of human evolution and social change, arizona state.
First, it is important to understand that mdr is an evolving paradigm, featuring a series of mechanisms including drug related factors drug transport and metabolism, alterations in drug targets and cell responserelated factors dna damage repair, intrinsic adaptive responses promoting survival and resistance, a wider chemical view of the. Cancer drug resistance can be divided into intrinsic and acquired resistance. For example, in environmentally mediated drug resistance emdr, components of tumor mesenchyma protect cancer cells from what would otherwise be lethal concentrations of cytotoxic drugs meads et al. Autophagy can be a doubleedged sword for mdr tumors. The current paradigm suggests that a combination of environmental. Chemotherapy resistance can arise due to several host or tumorrelated factors.
Overwhelming evidence has demonstrated that drug resistance is the primary cause of clinical treatment failure, because patients who have similar clinical characteristics are usually treated by standard protocols without considering individual responses holohan et al. This article was downloaded from harvard universitys dash. The changing landscape of phase i trials in oncology. The cancer stem cell marker aldehyde dehydrogenase is. Micrornas in neuroblastoma tumorigenesis, therapy resistance, and disease evolution. Mathematical modeling and computational prediction of cancer. A current challenge in cancer treatment is drug resistance. Caitriona holohan, sandra van schaeybroeck, daniel b. Intrinsic resistance occurs before receiving therapy, which limits the use of anticancer drugs. Johnston abstract resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to classical cytotoxic. Mechanisms of resistance to parp inhibitors an evolving challenge in. Abstract resistance to chemotherapy and molecularly targeted therapies is a major. Here, a new form of multidrug resistance, inducible drug glucuronidation, is discussed.
These include the initially developed docetaxel 10 yr ago, followed by sipuleucelt, abiraterone, cabazitaxel, enzalutamide, and radium223. Molecular and pharmacological mechanisms of drug resistance. However, their clinical benefit is typically shortlived because of the relatively rapid acquisition of drug resistance following treatment response. However, it suffers from drug efflux mediated by various drug transporter proteins and in many cases fails to produce curative clinical outcomes. 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. Overviews and methods contains chapters that cover topics such as. This work was supported by a grant from cancer research uk, c212a721. Nov 18, 2014 primary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy.
Karolina lapinska 2, mckenna longacre 3, nicole snyder 2 and sibaji sarkar 2, 1 school of human evolution and social change, arizona state university. Acquired resistance may develop during treatment even if some drugs have anticancer effects at the early stage 23. Deciphering the metabolic role of ampk in cancer multidrug. Lung cancer, classified as nonsmall cell lung cancer nsclc and smallcell lung cancer sclc, is the leading cause of cancer related death with highest morbidity and mortality in the united states 12. Autophagy and multidrug resistance in cancer cancer. The design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. 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 section is intended to introduce some of the main ways in which cancer cells can resist treatments. Benedetta colmegna, lavinia morosi, maurizio dincalci. This volume discusses the latest advancements and technologies used in cancer drug resistance research. The current paradigm suggests that a combination of environmental and. May 31, 2019 cancer drug resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc. However, most current research is focused on tumorspecific factors and specifically genes that handle expression of.
Dox is an anthracycline antibiotic that is the standard of care for many cancer patients. Similarly, tumor cells in regions of hypoxia may be protected as a result of increased expression of pgp, upregulation. Overall, drug inactivation is a mechanism of cancer drug resistance that warrants further. While drug resistance in cancer is thought to be driven by irreversible genetic mutations, emerging. Department of internal medicine and mageewomens research institute, university of pittsburgh, pittsburgh, pa, usa.
Accumulating preclinical and clinical data point to a role for a heterogeneous. Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advancedstage disease. Over the past few years, our repertoire of therapeutic options in metastatic castrationresistant prostate cancer mcrpc has expanded, with six novel therapies having a proven survival benefit. 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. Cancer is the second leading cause of death in the us. Emerging insights of tumor heterogeneity and drug resistance. Major physiological signaling pathways in the regulation of cell proliferation and survival.
Cancer drug resistance overviews and methods jose rueff. An overview the harvard community has made this article openly available. Holohan and others published longley db and johnston pg. Cancer drug resistance cancer drug discovery and development. Both clinical and experimental aspects of drug resistance in cancer are included. Among these factors, drug effluxmediated resistance due to overexpression of abc transporters is the most frequent occurrence 4. The role of exosomal microrna in cancer drug resistance. Unfortunately, clinical strategies to overcome these lag far behind. Targeted therapies in cancer and mechanisms of resistance.
Nice 3, haiyuan zhang 2, canhua huang 1 and yunlong lei 4. This is typically metastatic disease, which depends on systemic treatment. This mismatch likely underlies our inability to implement new durable treatment strategies. Platinum resistant cancers progressrecur in approximately 25% of cases within six months. Jan 11, 2011 evolution of cancer can shed light on drug resistance. A database of ovarian cancer transcriptomic datasets including treatment and response information was set up by mining the geo and. Correlation of long noncoding rna expression with metastasis, drug resistance and clinical outcome in cancer. Cancer drug resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc. We aimed to identify clinically useful biomarkers of platinum resistance. Overcoming drug resistance by targeting cancer bioenergetics. Monoclonal antibodies mabs are a rapidly evolving field in cancer therapy, however a. Drug resistance is caused by a variety of factors, such as cancer stem cells, drug efflux, drug inactivation, alterations in drug targets, dna damage repair, and deregulated apoptosis. Holohan c1, van schaeybroeck s, longley db, johnston pg. Multidrug resistance mdr occurs frequently after longterm chemotherapy, resulting in refractory cancer and tumor recurrence.
However, how resistance arises in cancer remains incompletely understood. 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. Another is a measure of the number of evolving cells in a tumor. Alexander j cole 1, adetunji p fayomi 1, vivian i anyaeche 2, shoumei bai 1, ronald j buckanovich 3. Holohan c, van schaeybroeck s, longley db, johnston pg 20 cancer drug resistance. Despite novel molecular therapies, the prognosis of nsclc, which accounts for 85% of cases, has low treatment response rates and poor. The functional significance of lipid metabolism in cancer cells is not fully understood. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Your story matters citation housman, genevieve, shannon byler, sarah heerboth, karolina lapinska, mckenna longacre, nicole snyder, and sibaji sarkar. Gottesman mm 2002 mechanisms of cancer drug resistance. What really matters response and resistance in cancer.
Mechanisms of drug resistance in cancer therapy mario mandala. An evolving paradigm resistance to chemotherapy and molecularly targeted therapies is a major. Resistance to treatment with anticancer drugs results from a variety of factors. 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. The mechanism of drug resistance is complicated because of interaction various factors including apoptosis, the epithelialmesenchymal transition emt, dna damage repair, targets mutation or alteration and drug inactivation and efflux, resulting in multidrug resistance mdr 4, 5. 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.
Drug resistance and the resulting ineffectiveness of the drug treatment are responsible for up to 90% of the cancer related deaths drug resistance in cancer is a wellknown phenomenon that results when cancer. Cancer cells rapidly evolve a multitude of defense mechanisms to evade the effects of the oncologists drug arsenal. Cancer drug resistance is an important cause of the often inevitable failure of targeted drug therapeutics in clinical anticancer treatment. Cd36mediated metabolic rewiring of breast cancer cells. View special issue articles cancer drug resistance.
Apigenin overcomes drug resistance by blocking the signal. What really matters response and resistance in cancer therapy. An evolving paradigm resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. Evolution of cancer can shed light on drug resistance. Understanding, predicting cancer evolution may open door to clinical research options. This is a very serious problem that may lead to recurrence of disease or even death. Autophagy, a selfdegradative system, universally arises during the treatment of sensitive and mdr cancer. An evolving paradigm of cancer stem cell hierarchies. Mek1 is associated with carboplatin resistance and is a. Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment. Even the most effective therapies often fail to produce a complete and durable tumor response and ultimately give rise to therapy resistance and tumor relapse. School of human evolution and social change, arizona state university. Resistance to anticancer drugs arises from a wide variety of factors, such as genetic mutations andor.
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