Blog
About

  • Record: found
  • Abstract: found
  • Article: not found

Resistance to chemotherapy: new treatments and novel insights into an old problem

Read this article at

ScienceOpenPublisherPMC
Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      Resistance to cancer chemotherapeutic treatment is a common phenomenon, especially in progressive disease. The generation of cellular models of drug resistance has been pivotal in unravelling the main effectors of resistance to traditional chemotherapy at the molecular level (i.e. intracellular drug inactivation, detoxifying systems, defects in DNA repair, apoptosis evasion, membrane transporters and cell adhesion). The development of targeted therapies has also been followed by resistance, reminiscent of an evolutionary arms race, as exemplified by imatinib and other BCR-ABL inhibitors for the treatment of chronic myelogenous leukaemia. Although traditionally associated with the last stages of the disease, recent findings with minimally transformed pretumorigenic primary human cells indicate that the ability to generate drug resistance arises early during the tumorigenic process, before the full transformation. Novel technologies, such as genome profiling, have in certain cases predicted the outcome of chemotherapy and undoubtedly have tremendous potential for the future. In addition, the novel cancer stem cell paradigm raises the prospect of cell-targeted therapies instead of treatment directed against the whole tumour.

      Related collections

      Most cited references 47

      • Record: found
      • Abstract: found
      • Article: not found

      MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.

      The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        Multidrug resistance in cancer: role of ATP-dependent transporters.

        Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Tumour stem cells and drug resistance.

          The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.
            Bookmark

            Author and article information

            Affiliations
            [1 ]simpleMRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Du Cane Road, London W12 0NN, UK
            [2 ]simpleDivision of Surgery, Oncology, Reproductive Biology and Anaesthetics, Department of Oncology, Imperial College Faculty of Medicine, Hammersmith Hospital Du Cane Road, London W12 0NN, UK
            Author notes
            [* ]Author for correspondence: ernesto.yague@ 123456imperial.ac.uk
            Journal
            Br J Cancer
            British Journal of Cancer
            Nature Publishing Group
            0007-0920
            1532-1827
            29 July 2008
            29 July 2008
            5 August 2008
            : 99
            : 3
            : 387-391
            2527800
            18665178
            6604510
            10.1038/sj.bjc.6604510
            Copyright 2008, Cancer Research UK
            Categories
            Minireviews

            Comments

            Comment on this article