Table 2.
Mechanisms of docetaxel resistance in prostate cancer
| Unfavorable tumor microenvironment |
| Disorganized tumor blood vessels lead to impaired drug distribution |
| Increased interstitial fluid pressure impedes intra-tumoral drug delivery |
| Hypoxic areas of tumor are slowly proliferating and resistant to cell-cycle-dependent drugs |
| Tumor hypoxia may select for cancer cells with overexpression of survival pathways |
| Amplification of paracrine growth loops between tumor cells and stromal cells |
| Adhesion of cancer cells to each other and to extracellular matrix |
| EMT and acquisition of stemness properties |
| Drug efflux pump |
| Docetaxel has high substrate affinity for P-glycoprotein, the dominant drug efflux pump |
| Cancer cells that synthesize P-glycoprotein are resistant to docetaxel and paclitaxel |
| Resistance is conferred by overexpression of the MDR1 gene |
| Additional drug export pumps include ABCB4 (encoded by MDR2) and ABCC1 (encoded by MRP1) |
| Alterations in microtubule structure and/or function |
| β-Tubulin mutations that affect docetaxel binding |
| Increased total cellular β-tubulin content or overexpression of certain β-tubulin isotypes (for example, βIII-tubulin) |
| Post-translational β-tubulin modifications |
| Altered expression of microtubule-destabilizing phosphoproteins |
| Promotion of microtubule-based microtentacles |
| Overexpression of microtubule-associated proteins |
| Altered interaction between microtubules and other cytoskeletal components (for example, γ-actin) |
| Apoptotic defects |
| Upregulation of Bcl-2 and clusterin |
| Increased expression of lipid kinases (for example, sphingosine kinase-1) and serine-threonine kinases (for example, Pim-1 kinase) |
| Activation of the PTEN/PI3K/mTOR pathway |
| Activation of the MAPK/ERK pathway |
| Activation of other pathways (for example, Hedgehog, β-catenin, IL-6, EGFR, endothelin, somatostatin pathways) |
Abbreviations: ABCB4, ATP-binding cassette B4; EGFR, epidermal growth factor receptor; EMT, epithelial–mesenchymal transition; ERK, extracellular signal-regulated kinase; IL, interleukin; MAPK, mitogen-activated protein kinase; MDR1, multi-drug resistance gene; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome ten.