Background


II.    Drug resistance in cancer and in MM


Tumor drug resistance involves both intrinsic mechanisms in tumor cells and extrinsic microenvironment-mediated protection.


Intrinsic mechanisms of drug resistance in tumor cells.

These mechanisms can be classified into 4 categories.


1) Efflux transporters in tumor cells and drug resistance.


Multidrug resistant transporters extrude large hydrophobic cytotoxic agents from cancer cells, and are ATP binding cassette (ABC) proteins, of which 3 major types found in humans are members of the ABCB (ABCB1/MDR1/P-glycoprotein), ABCC (ABCC1, ABCC2, probably ABCC306, 10-11) and ABCG (ABCG2) subfamilies, with multiple members in each (Sarkadi et al. 2006). Upregulated transporter expression mediates resistance in cancer cells by ATP-dependent extrusion of chemotherapeutic drugs.


2) Gene mutations, gene and miRNA expression in tumor cells and drug resistance.


The most striking example of mutation conferring drug resistance is in the BCR-ABL fusion protein, which is oncogenic and drives chronic myeloid leukemia (CML) growth. The BCRABL fusion protein can be potently blocked by Imatinib kinase inhibitor, but mutations in it allow its escape (Quintas-Cardama et al. 2009). The hypoxia-inducible factor HIF1α has been associated with chemosensitivity and regulates p53 activity, raising the potential for p53 mutations to restrict efficacy of use of HIF1α inhibitors (Rohwer et al. 2010).


Genomic mutations and their role in cancer are now being examined at a hitherto unparalleled level, made possible by the availability of the draft human genome in 2000 (McDermott et al. 2011) and decreasing costs by several orders of magnitude. Many cancer genomes are under evaluation by the International Cancer Genome Consortium [http://icgc.org]. Two models have emerged of cancer origins. In the first, mutations are characterized as either ‘drivers’ or ‘passengers’ in transformation, and cancer progression occurs by sequential stepwise acquisition of drivers mutations in subclones which dominate growth (Stratton et al. 2009). In the second, seen less frequently, i.e. in 2%-3% of all cancers and in ~25% of bone cancers, malignant transformation is driven by a single catastrophic event, termed chromothripsis (‘chromosome’ – ‘shattering’), where genomic aberrations occur at a scale incompatible with stepwise acquisition (Stephens et al. 2011).


The role of miRNA in drug resistance in cancer is also emerging as significant (Zheng et al. 2010). Imbalanced miRNA expression can mediate a multitude of cellular effects, such as regulating apoptosis. In Multiple Myeloma, miRNA expression in primary MMCs is linked with high risk (Zhou et al. 2010), but the mechanisms of action of the prognostic miRNA have yet to be characterized.


3) Signaling pathways, apoptosis and drug resistance.


Apoptosis and its abrogation in cancer cells have also been delineated as mechanisms that promote resistance to drugs. MCL-1 leukemic cells are more sensitive to chemotherapy than their BCL-2 counterparts (Brunelle et al. 2009). Autophagy is a complex response in cancer cells involving pro-death and pro-survival signals in response to cell death inducing agents and is currently under evaluation as a mechanism of drug resistance (Dalby et al. 2010).


4) Tumor stem cell and drug resistance


The stem cell question in cancer has attracted much attention recently, and has been proposed as relevant to understanding drug resistance, as a quiescent cell that escapes therapy (Blanpain et al. 2011; Dick 2008). In Multiple Myeloma, there is no formal identification of tumor stem cells able to propagate the disease. Most MM research teams, including OVER-MyR partners, failed to identify any such precursor (Perez-Andres et al. 2010; Pfeifer et al 2011).


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