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

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.

Figure 1

Cellular model of tumorigenesis and pretumorigenic drug resistance. (A) This model was first described by Hahn et al (1999) in human BJ fibroblasts and embryonic kidney epithelial cells. Normal cells are transformed by expressing the catalytic subunit of telomerase (to avoid replicative senescence), SV40 LT (which binds and inactivates the tumour suppressors p53 and pRb controlling the DNA repair and G1 cell-cycle checkpoints, respectively) and ST (which binds and inactivates PP2A, a serine/threonine phosphatase involved in several signalling pathways) proteins and oncogenic ras. Since then, the model has been validated by transforming primary epithelial cells from breast, prostate, ovary and lung (Boehm and Hahn, 2005). (B) Complete tumorigenic transformation is not a prerequisite for the acquisition of drug resistance. When a series of pretumorigenic and minimally transformed tumorigenic cells derived from human embryonic skin fibroblasts are treated with doxorubicin, drug-resistant cells can be obtained from fully tumorigenic as well as pretumorigenic cells. Cells at the early stages of transformation, that is, those in which hTERT (telomerase) has been ectopically expressed, do not die due to the action of the drug, but become senescent (drug-induced sencescence). Disruption of the pathways controlled by the tumour suppressors p53 and pRb is necessary and sufficient to set the conditions for the acquisition of drug resistance. The diagram is based on data from Yagüe et al (2007).