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      Drug Resistance in Cancer: An Overview

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          Abstract

          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 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, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study.

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          Most cited references84

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          Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis.

          Noa Rivlin, Ran Brosh, Moshe Oren … (2011)
          Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages. Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation, thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis. Here, the authors review the different studies on the involvement of p53 inactivation at various stages of tumorigenesis and highlight the specific contribution of p53 mutations at each phase of cancer progression.
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            Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.

            A.H. Schinkel, J.J.M. Smit, O van Tellingen … (1994)
            We have generated mice homozygous for a disruption of the mdr1a (also called mdr3) gene, encoding a drug-transporting P-glycoprotein. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectin (100-fold) and to the carcinostatic drug vinblastine (3-fold). By comparison of mdr1a (+/+) and (-/-) mice, we found that the mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many tissues (especially in brain) and in decreased drug elimination. Our findings explain some of the side effects in patients treated with a combination of carcinostatics and P-glycoprotein inhibitors and indicate that these inhibitors might be useful in selectively enhancing the access of a range of drugs to the brain.
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              Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer.

              Rosalyn A. Juergens, John Wrangle, Frank P. Vendetti … (2011)
              Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy. This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 05 September 2014
                Publication date Collection: September 2014
                Volume: 6
                Issue: 3
                Pages: 1769-1792
                Affiliations
                [1 ]School of Human Evolution and Social Change, Arizona State University, Tempe, AZ 85287, USA; E-Mail: ghousman@ 123456asu.edu
                [2 ]Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; E-Mails: sbyler@ 123456bu.edu (S.B.); heerboth@ 123456bu.edu (S.H.); karolka@ 123456bu.edu (K.L.); nsnyder@ 123456bu.edu (N.S.)
                [3 ]Harvard Medical School, Boston, MA 02115, USA; E-Mail: Mckenna_Longacre@ 123456hms.harvard.edu
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: ss1@ 123456bu.edu ; Tel.: +1-617-638-5630; Fax: +1-617-638-5609.
                Article
                Publisher ID: cancers-06-01769
                DOI: 10.3390/cancers6031769
                PMC ID: 4190567
                PubMed ID: 25198391
                SO-VID: 05fccacc-3708-426b-856d-4cc683d607a0
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 15 July 2014
                Date revision received : 25 August 2014
                Date accepted : 29 August 2014
                Categories
                Subject: Review

                Keywords: cancer,drug resistance,epigenetics,methylation,cancer progenitor cells,combination therapy,review
                Data availability:
                Keywords: cancer, drug resistance, epigenetics, methylation, cancer progenitor cells, combination therapy, review

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