Taxane resistance in prostate cancer is mediated by decreased drug-target engagement

Abstract

and intricate microtubule network into dense microtubule bundles that can be readily visualized by fluorescence microscopy. Microtubules are highly dynamic filaments fulfilling a number of functions in interphase, such as intracellular trafficking and signaling. They are also critically involved in the formation of the mitotic spindle that facilitates chromosome segregation during mitosis, so that taxane treatment results in aberrant mitotic arrest and apoptotic cell death (5). Although this mitotic arrest is a major mechanism of action in cell culture, there is some controversy as to whether mitotic arrest is the key mechanism underlying the clinical activity of taxanes in patients where the mitotic rate of growing tumors is significantly lower than in cultured cell lines (6, 7). Along these lines, we have shown important functions for microtubules in interphase cells, including nuclear translocation of transcription factors (8, 9), inhibition of which by taxane treatment can be lethal irrespective of mitosis. Thus, taxane treatment may lead to cell death in mitosis or in interphase (10).Understanding the mechanism of taxane resistance has been a topic of intense investigation over the last 2 decades. Although there are numerous reports on mechanisms of taxane resistance in preclinical models, there are very few studies addressing the effects of taxanes in vivo in patient tissue (11,12). Possible mechanisms of taxane resistance fall broadly into 2 groups. One group is mechanisms that result in lack of drug-target engagement so that microtubules are not stabilized and microtubule bundles are not formed. One example in this group is alterations in microtu-

Mechanisms of Taxane Resistance

“…Some have suggested that cancer cells recognize a stress signal following taxane treatment and respond with upregulating isotypes of tubulin that allow them to increase MT dynamics, upregulate survival signaling pathways, or evade forced apoptosis [ 339 ]. One study quantified the amount of polymerized and stable MTs that self-arrange in clumps or bundles, known as MT bundling, that occurs in taxane-sensitive or taxane-resistant tumors following treatment [ 340 , 341 ]. The amount of bundling was then correlated with the documented responsiveness of the patient to therapy, where decreased bundling was observed in patients that had recorded resistance to therapy.…”

“…In fact, studies have demonstrated that cells derived from DTX-treated CRPC patients lack AR nuclear localization and that MTs directly bind to AR [ 348 , 349 , 350 ]. There is evidence that the amount of nuclear localization of AR negatively correlates with clinical responsiveness to taxane treatment, where cytoplasmic sequestration of AR is associated with increased MT bundling and increased response to taxanes [ 341 , 351 ]. Likewise, there is a connection between DTX resistance and increased AR signaling [ 335 ], indicating an association between taxane efficacy and the AR signaling pathway mediated by MTs.…”

Molecules and Mechanisms to Overcome Oxidative Stress Inducing Cardiovascular Disease in Cancer Patients

“…Taxanes, belonging to a class of diterpenes with antineoplastic effects, are plant alkaloids. They are microtubule-stabilizing compounds that inhibit mitosis of cancer cells and interfere with a number of biochemical pathways to induce apoptosis and cancer cell death [ 34 , 35 ]. Among all the classes of antineoplastic agents, taxanes are one of the most widely used representing a cornerstone of chemotherapy.…”

<p>Aptamer-Functionalized Dendrimer Delivery of Plasmid-Encoding lncRNA <em>MEG3</em> Enhances Gene Therapy in Castration-Resistant Prostate Cancer</p>

“…1,2 However, patients may develop severe complications, iatrogenic injury, drug toxicity, and therapy resistance. 3,4 Castration-resistant PCa (CRPC) is considered the terminal stage of the disease, 5 and prolonging the occurrence of castration-resistant malignancy remains therapeutically challenging. Gene therapy has been deployed to deliver specific nucleotide sequences to target cells, where they can correct or compensate for the existing gene defect or abnormality that leads to specific diseases or inhibit the expression of oncoproteins.…”

“… 1 , 2 However, patients may develop severe complications, iatrogenic injury, drug toxicity, and therapy resistance. 3 , 4 …”