Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC. Mol Cancer Ther; 16(10); 2257–66. ©2017 AACR.
Mortality from advanced or metastatic prostate cancer remains as a significant clinical challenge. Patients initially respond to androgen-deprivation therapy (ADT), but inevitably progress to incurable castration-resistant disease (1). The standard of care for castration-resistant prostate cancer (CRPC) has been docetaxel-based chemotherapy regimens. Despite a demonstrated survival benefit, about 50% of patients do not respond initially and those that do eventually fail treatment due to the development of resistance (2).
Recent efforts have added novel therapies that have augmented our ability to treat advanced CRPC. Enzalutamide, abiraterone, sipuleucel-T, and radium-223 have been shown to provide a survival benefit and may be administered before or after treatment with docetaxel (3–8). Cabazitaxel, a next-generation taxane, was also shown to provide a survival benefit but is approved only to treat docetaxel pretreated patients (9). Despite these improvements in care, patients eventually progress and still succumb to the disease highlighting three key concerns. First, it is not known what sequence to use these treatments in for optimized care, nor is it known which combinations will produce the most benefit. Second, presentation with or the development of resistance is inevitable which ultimately renders these new agents ineffective. Finally, the issue of potential cross-resistance between available therapies further complicates treatment decisions. It is imperative that these questions be addressed.
Elucidating and understanding mechanisms of acquired drug resistance and subsequent cross-resistance to other available therapies will greatly improve our ability to treat advanced CRPC patients. The mechanisms of resistance to docetaxel have been investigated and shown to include loss of p53 functioning, increased expression of β-tubulin isoforms, decreased expression of BRCA1, and increased expression of the drug efflux pump ABCB1 (10–12). Mechanisms of cabazitaxel resistance are lesser known but are thought to include the presence of the retinoblastoma protein and loss of the membrane transporter SLCO1B3 (13, 14). Whether there exists cross-resistance between docetaxel and cabazitaxel is poorly understood. Although it has been shown that cabazitaxel is beneficial post-docetaxel, the survival benefit is modest (9). It may be that responses to cabazitaxel are blunted by common mechanisms of resistance with docetaxel. Ascertaining this information is critical for the rational design of treatment regimens leading to improved outcomes and prolonged survival.
Our previous work investigated mechanisms of resistance to docetaxel in prostate cancer and found that ABCB1 overexpression mediates robust resistance to this drug (12). In this study, we explore whether cross-resistance between docetaxel and cabazitaxel exists and its potential underlying mechanisms in advanced prostate cancer. Our data demonstrate that docetaxel-resistant prostate cancer cells exhibit cross-resistance to cabazitaxel and that this cross-resistance is mediated through ABCB1. Strategies to inhibit ABCB1 function are capable of resensitizing cells to cabazitaxel treatment thus highlighting new combinations that may be efficacious for prostate cancer treatment. Finally, we show that combination strategies are more effective with cabazitaxel than with docetaxel thus providing a potential rationale to favor cabazitaxel over docetaxel rechallenge in the clinic.
Materials and Methods
Cell culture and reagents
DU145 cells were obtained from the ATCC in 2008. C4-2B cells were kindly provided by Dr. Leland Chung (Cedars-Sinai Medical Center, Los Angeles, CA) in 2005. Short tandem repeat (STR) analysis was used for testing and authentication of the cell lines. All experiments with these cell lines and their derivatives were conducted within 6 months of receipt or resuscitation after cryopreservation. Cells were maintained in RPMI1640 media supplemented with 10% FBS, 100 U/mL penicillin, and 0.1 mg/mL streptomycin. TaxR and DU145-DTXR cells were described previously and maintained in complete RPMI1640 supplemented with 5 nmol/L docetaxel (12, 15). C4-2B and DU145 cells were cultured alongside TaxR and DU145-DTXR cells as respective appropriate controls. TaxR-control and TaxR-shABCB1 cells were described previously and maintained in complete RPMI1640 media supplemented with 2 μg/mL puromycin (12). All cells were maintained at 37°C in a humidified incubator with 5% carbon dioxide. Puromycin (catalog no.: BP2956-100) was purchased from Thermo Fisher Scientific. Docetaxel (catalog no.: RS019) was purchased from TSZ CHEM. Cabazitaxel (catalog no.: S3022) was purchased from Selleckchem. Elacridar (catalog no.: 143664-11-3) was purchased from Sigma-Aldrich. Bicalutamide (catalog no.: B3209) was purchased from LKT Laboratories. Enzalutamide (catalog no.: S1250) was purchased from Selleckchem.
Cell growth assay
For all cell growth assays described, cells were plated at a density of 30,000 cells per well in 24-well plates in complete RPMI1640 media without any selection agent. After 24 hours, cells were subjected to indicated single or combination treatments. Unless otherwise noted in the text, docetaxel (DTX) = 1 nmol/L, cabazitaxel (CTX) = 1 nmol/L, elacridar (Elac) = 0.5 μmol/L, bicalutamide (Bic) = 10 μmol/L, and enzalutamide (Enz) = 10 μmol/L. Seventy-two hours posttreatment, total cells were counted via coulter counter. Cell counts were normalized to control cell growth treated only with vehicle (DMSO). Data are displayed as cell survival rate as the percentage of control cell growth. Cell survival rate (%) = (Treatment group cell number/Control group cell number) × 100. All conditions were performed in triplicate. All experiments were performed at least twice.
For all clonogenic assays described, cells were plated at 500 cells per well in 6-well plates in complete RPMI1640 with no selection agent. Plated cells were subsequently treated 24 hours later as indicated. Unless otherwise noted in the text, docetaxel = 1 nmol/L, cabazitaxel = 1 nmol/L, elacridar = 0.5 μmol/L, bicalutamide = 10 μmol/L, and enzalutamide = 10 μmol/L. Colonies were allowed to form for 8–14 days as indicated. At the completion of each assay, cell colonies were washed in PBS and then fixed in 100% methanol for 10 minutes. This was followed by staining using 0.5% crystal violet for 10 minutes. After staining, colonies were counted. Data are displayed as a percentage of control cell colony growth [control is vehicle (DMSO) treatment only]. All conditions were performed in duplicate. All experiments were performed at least twice.
WST-1 proliferation assay
Cells were plated at a density of 30,000 cells per well in 24-well plates in complete RPMI1640 media without any selection agent. After 24 hours, cells were subjected to indicated single or combination treatments; cabazitaxel = 1 nmol/L, bicalutamide = 10 μmol/L, enzalutamide (Enz) = 10 μmol/L. Seventy-two hours posttreatment, cell proliferation was assessed via WST-1 assay purchased from Takara Bio (catalog no.: MK400) according to the manufacturer's protocol. Cell proliferation was normalized to control cell proliferation treated only with vehicle (DMSO). Data are displayed as proliferation rate as the percentage of control. Cell proliferation rate (%) = (Treatment group proliferation/Control group proliferation) × 100. All conditions were performed in triplicate. All experiments were performed at least twice.
Preparation of whole-cell extracts
Cells were harvested, washed with PBS, and lysed in high-salt buffer (10 mmol/L HEPES pH 7.9, 0.4 mol/L NaCl, 1 mmol/L EDTA, 0.5 mmol/L PMSF, 1 mmol/L DTT, 1 mmol/L NaV, 20 mmol/L NaF, 1 mmol/L EGTA, 20% glycerol) with a freeze–thaw procedure. High salt buffer was supplemented with protease inhibitors (catalog no.: 11836153001) purchased from Sigma-Aldrich. Protein concentration was determined with Pierce Coomassie Plus (Bradford) Assay Kit (catalog no.: 23236) purchased from Thermo Fisher Scientific.
Western blot analysis
Whole-cell protein extracts were resolved by SDS-PAGE and proteins were transferred to nitrocellulose membranes. After blocking for 1 hour at room temperature in 5% milk in PBS/0.1% Tween-20, membranes were incubated overnight at 4°C with the indicated primary antibodies. ABCB1 antibody (SC-8313, rabbit-polyclonal, 1:500 dilution) was purchased from Santa Cruz Biotechnology. PARP antibody (9542, rabbit-polyclonal antibody, 1:1,000 dilution) was purchased from Cell Signaling Technology. Cleaved-PARP antibody (9541, rabbit-polyclonal antibody, 1:1,000 dilution) was purchased from Cell Signaling Technology. Tubulin (T5168, mouse mAb, 1:6,000 dilution) was purchased from Sigma-Aldrich. Tubulin was used to monitor the amounts of samples applied. Following secondary antibody incubation, proteins were visualized with a chemiluminescence detection system (catalog no.: WBLUR0500) purchased from Millipore.
All quantitated data are displayed as the percentage of control mean ± SD. Significance was assessed using a two-tailed two sample equal variance Student t test. A P value of ≤0.05 was accepted as significant.
Docetaxel-resistant prostate cancer cells are cross-resistant to cabazitaxel
Our previous work used C4-2B and DU145 docetaxel-resistant derivative cell lines (hence forth referred to as TaxR and DU145-DTXR, respectively) to investigate mechanisms of resistance (12, 15). Clinically, cabazitaxel is approved to treat patients who have progressed during or after docetaxel chemotherapy (16). Whether docetaxel resistance confers any cross-resistance to cabazitaxel treatment is unclear. Thus, we tested whether docetaxel-resistant cell lines would respond to cabazitaxel. TaxR and DU145-DTXR cells were subjected to cell growth assays using a cabazitaxel dose curve to assess response to treatment versus parental C4-2B and DU145 cells, respectively. We found that in both TaxR and DU145-DTXR cells, response to cabazitaxel was blunted compared with their respective parental cells (Fig. 1A). The IC50 of C4-2B cells to cabazitaxel was 0.7 nmol/L, whereas the IC50 of TaxR cells to cabazitaxel was 7.3 nmol/L, an approximate 10-fold increase. The IC50 of the DU145 cells was 0.7 nmol/L, whereas the IC50 for DU145-DTXR cells was 3.3 nmol/L, an approximate 5-fold increase. These data were confirmed using colony formation assays. We found that parental cell lines were completely unable to form colonies even at the lowest tested dose of 0.5 nmol/L cabazitaxel, whereas TaxR and DU145-DTXR cells were far less affected (Fig. 1B). Western blots for PARP and cleaved-PARP indicate that cabazitaxel's ability to induce apoptosis is decreased in TaxR and DU145-DTXR cells further demonstrating resistance to treatment (Fig. 1C). These data demonstrate that docetaxel-resistant cells are cross-resistant to cabazitaxel. This suggests that mechanisms involved in docetaxel resistance may be shared by cabazitaxel. However, resistance to cabazitaxel is not as robust as that to docetaxel, as both TaxR and DU145-DTXR cells are completely resistant to 5 nmol/L docetaxel but do exhibit some response to the same dose of cabazitaxel (Fig. 1D). Thus, our model mimics clinical findings in that cabazitaxel retains efficacy post-docetaxel. However, clinical responses may be blunted by mechanisms of cross-resistance.
Inhibition of ABCB1 resensitizes docetaxel-resistant cells to cabazitaxel
Our previous work demonstrated that ABCB1 expression was increased in both TaxR and DU145-DTXR cells versus parental cells and that this increased expression was responsible for mediating resistance to docetaxel (Fig. 2A, left; ref. 12). ABCB1 is a cell membrane efflux protein responsible for pumping a wide array of substrates out of cells and is known to be able to confer resistance to several chemotherapeutic drugs including docetaxel, doxorubicin, and paclitaxel (17). Whether ABCB1 mediates resistance to cabazitaxel in prostate cancer is unclear. To determine whether increased expression of ABCB1 is responsible for cross-resistance to cabazitaxel, we used TaxR cells stably expressing an shRNA against ABCB1 (TaxR-shABCB1) and subjected them to cabazitaxel treatment. Cells expressing an shRNA against GFP (TaxR-control) served as a control. We first demonstrate that ABCB1 protein levels are decreased in TaxR-shABCB1 versus TaxR-control (Fig. 2A, right). Growth assays clearly demonstrate that TaxR-shABCB1 cells are resensitized to 1 nmol/L cabazitaxel treatment versus TaxR-control cells (Fig. 2B). These data were further supported with colony formation assays, which showed that downregulation of ABCB1 expression using an shRNA specific to ABCB1 resensitized TaxR cells to cabazitaxel treatment (Fig. 2C). Western blots for cleaved PARP demonstrate that TaxR-shABCB1 cells undergo significant apoptosis compared with control cells when exposed to cabazitaxel (Fig. 2D). These data suggest that ABCB1 can mediate resistance to cabazitaxel, and that ABCB1 is a critical mechanism of cross-resistance between cabazitaxel and docetaxel.
To further demonstrate that ABCB1 mediates resistance to cabazitaxel, we used elacridar, a small-molecule inhibitor of ABCB1. Our previous work demonstrated that elacridar could effectively inhibit ABCB1 activity and render docetaxel-resistant cells sensitive to treatment (12, 15). Cell growth assays demonstrate that we can resensitize both TaxR and DU145-DTXR cells to 1 nmol/L cabazitaxel treatment using pharmacologic ABCB1 inhibition via elacridar (Fig. 3A). We additionally demonstrate that elacridar restores the cell death response to cabazitaxel treatment through Western blots for cleaved PARP (Fig. 3B). Taken together, these results support a role for ABCB1 in mediating resistance to cabazitaxel and cross-resistance between taxanes in prostate cancer.
Antiandrogen–mediated inhibition of ABCB1 function sensitizes to cabazitaxel
Previous work demonstrates novel functionality of the antiandrogens bicalutamide and enzalutamide in blocking ABCB1 function through inhibition of its ATPase activity (15). Furthermore, it was shown that inhibition of ABCB1 functioning using either bicalutamide or enzalutamide could resensitize docetaxel-resistant cells to docetaxel treatment (15). Because we showed that increased ABCB1 expression and activity is a common mechanism of resistance to taxanes, we hypothesized that we could use a similar strategy to resensitize these cells to cabazitaxel treatment through anti-androgen–mediated inhibition of ABCB1 ATPase activity. Cell growth assays using bicalutamide (10 μmol/L), cabazitaxel (1 nmol/L), or combinations of bicalutamide with cabazitaxel demonstrate that bicalutamide could indeed resensitize both TaxR and DU145-DTXR cells to cabazitaxel treatment (Fig. 4A). These data were confirmed by colony formation assays that robustly show the ability of bicalutamide to increase the efficacy of cabazitaxel (Fig. 4B).
Similar tests were carried out to assess the ability of enzalutamide to affect sensitivity to cabazitaxel in both TaxR and DU145-DTXR cells. Like bicalutamide, cell growth assays demonstrate that enzalutamide (10 μmol/L) could re-sensitize both cell lines to cabazitaxel (Fig. 5A). Also, a combination treatment with either bicalutamide or enzalutamide with cabazitaxel could increase the cell death response of TaxR and DU145-DTXR cells as indicated by increased expression of cleaved-PARP (Fig. 5B). WST-1 assays further demonstrate that combinations of either bicalutamide or enzalutamide with cabazitaxel greatly reduce cellular proliferation versus any single-agent treatment (Fig. 5C). Taken together, these data demonstrate that resistance to cabazitaxel may be overcome through combinations with antiandrogen drugs.
Resensitization to cabazitaxel is more effective than that to docetaxel rechallenge
Because inhibition of ABCB1 resensitizes taxane-resistant cells to both docetaxel and cabazitaxel, we sought to understand whether resensitization to one drug is more effective than the other. Docetaxel rechallenge has been demonstrated clinically effective in certain instances and thus, it is of interest to ask which is a better strategy; a resensitizing agent in combination with (i) a docetaxel rechallenge or (ii) a switch to cabazitaxel (18). Our previous data demonstrated that antiandrogens could resensitize docetaxel resistant cells to 10 nmol/L docetaxel (15). Here, using additional cell growth assays, we tested lower doses (1 nmol/L) of either docetaxel or cabazitaxel in combination with 10 μmol/L bicalutamide (Fig. 6A). We found that combination with cabazitaxel was superior to docetaxel at this dose. In fact, we found little to no effect with 1 nmol/L docetaxel plus bicalutamide. However, a higher dose of 5 or 10 nmol/L docetaxel in combination with bicalutamide is effective as shown, consistent with results from a previous study (Fig. 6B; ref. 15). Thus, although bicalutamide can resensitize docetaxel-resistant cells to docetaxel treatment, combinations with cabazitaxel are more effective. Colony formation assays further demonstrate that combination with cabazitaxel far outperforms a similar combination with docetaxel (Fig. 6C). We also tested combinations of 1 nmol/L docetaxel or cabazitaxel with 10 μmol/L enzalutamide and found that again, combination with cabazitaxel outperformed combination with docetaxel (Fig. 6D). These data suggest that cabazitaxel combinations with either bicalutamide or enzalutamide are superior to similar combinations using docetaxel.
In this study, we have demonstrated that the docetaxel-resistant C4-2B and DU145 cell line derivatives TaxR and DU145-DTXR are cross-resistant to the next-generation taxane cabazitaxel. We show that resistance to cabazitaxel is mediated through increased expression of ABCB1 and that inhibition of ABCB1 functioning either with a small-molecule inhibitor (elacridar) or antiandrogens (bicalutamide and enzalutamide) can resensitize resistant cells to cabazitaxel treatment. Our work addresses key concerns regarding cross-resistance between docetaxel and cabazitaxel for advanced prostate cancer and highlights a common resistance mechanism involving ABCB1 that may be employed by prostate tumors to circumvent the activity of cabazitaxel. We additionally demonstrate the potential in using combinations of antiandrogens with cabazitaxel for increased effect.
Clinically, cabazitaxel is approved only for the treatment of patients who have previously undergone docetaxel treatment (9, 16). The TROPIC clinical trial demonstrated an improved overall survival using cabazitaxel in patients progressing during or after docetaxel treatment. Although these results are encouraging, the survival benefit is modest (2.4 months; ref. 9). Our data support these findings, showing that docetaxel-resistant prostate cancer cells are completely resistant to higher doses of docetaxel while still responding to some doses of cabazitaxel (Fig. 1D). However, we show a clear decrease in response to cabazitaxel in docetaxel resistant cells versus parental cells, demonstrating the existence of cross-resistance between docetaxel and cabazitaxel (Fig. 1). Thus, although clinical data demonstrate a clear benefit to using cabazitaxel post docetaxel, it is important to understand potential mechanisms of cross-resistance and design strategies to mitigate or overcome potential treatment impediments.
ABCB1 is an ATP-dependent membrane efflux pump that is known to act on many substrates (19). Furthermore, its upregulated expression is known to correlate with a poor prognosis and disease progression in varying types of cancer, including ovarian and bladder (20, 21). In prostate cancer, ABCB1 has also been shown to be upregulated versus noncancerous tissue and to positively correlate with disease stage and grade (22, 23). Our previous work demonstrated that ABCB1 is dramatically upregulated in docetaxel-resistant prostate cancer cells, that ABCB1 mediates resistance to treatment, and that inhibition of ABCB1 resensitizes these cells to docetaxel treatment (12, 15). Here, using both shRNA and small-molecule (elacridar) inhibition strategies, we show that this increased ABCB1 expression can mediate cross-resistance to cabazitaxel. Although it is possible that shRNA off-target effects may have influenced our data, our use of proper controls and multiple methods for inhibiting ABCB1 make us confident that in fact, ABCB1 is a significant factor in resistance to cabazitaxel (24). Interestingly, TaxR cells are more resistant to cabazitaxel than are DU145-DTXR cells and express much higher levels of ABCB1 (Fig. 2A, left). Although additional, unknown mechanisms of resistance may account for this finding, our data suggest the possibility that cabazitaxel resistance may be a function of ABCB1 expression. Further study is needed to fully understand the clinical significance of ABCB1 expression on response to taxane treatment. Fully understanding to what degree ABCB1 expression levels mediate resistance to each drug may allow for stratification of patients between the two or lead to decisions to try alternative therapies, thus preventing decisions to treat when success is unlikely. Proof-of-principle studies detecting higher ABCB1 levels in blood or serum samples from docetaxel-resistant prostate cancer patients have been performed thus making it feasible considering our novel findings to continue studying ABCB1 expression as a prognostic marker of taxane sensitivity (25, 26).
Our previous study highlighted the ability of the antiandrogen dugs bicalutamide and enzalutamide to inhibit ABCB1 function through inhibition of its ATPase activity (15). Furthermore, we demonstrated that use of antiandrogens resensitizes docetaxel resistant cells to docetaxel. We show in this study that these same antiandrogens are also able to re-sensitize docetaxel-resistant cells to cabazitaxel treatment, suggesting that combinations of drugs currently used for CRPC may be more beneficial than single agents. Our study further shows that cabazitaxel is more efficacious than docetaxel in combination with an antiandrogen in the setting of docetaxel resistance. Thus, our findings suggest that a combination of cabazitaxel with an ABCB1 inhibiting agent, such as an antiandrogen, should be preferred over a similar strategy with docetaxel rechallenge.
Because of the possibility of clinical cross-resistance between docetaxel and cabazitaxel, it is of interest to investigate which taxane would be better when given in the chemotherapy-naïve setting. Cabazitaxel is currently approved only to treat patients who have undergone docetaxel treatment. Recent analysis of data from the FIRSTANA clinical trial, which tests cabazitaxel directly against docetaxel in chemotherapy-naïve patients, demonstrated that there was no difference in outcome between use of the two taxanes (27). Because cabazitaxel has been shown effective post-docetaxel but is not superior in the chemotherapy-naïve setting, it is unlikely that cabazitaxel would become a first-line therapy. These data in conjunction with our findings suggest important clinical implications in which combination of cabazitaxel with anti-androgens is warranted. Although cabazitaxel alone is a second-line treatment for post-docetaxel CRPC, our work suggests that combination of cabazitaxel with an antiandrogen may improve its efficacy in this setting.
Another implication from our studies is whether antiandrogens should be routinely included in chemohormonal treatment regimens in the hormone-sensitive setting preceding the development of CRPC. Our data suggest that this may be a strategy for inhibiting the onset of docetaxel resistance through inhibition of ABCB1 function, thus potentially further augmenting the utility of this therapeutic regimen. Results from the CHAARTED and STAMPEDE clinical trials demonstrate a clear and robust increase in overall survival when docetaxel is given upfront with androgen deprivation therapy (ADT) for patients with 4 or more metastases or visceral disease (28, 29). Whether adding an antiandrogen to this treatment is beneficial is unknown. Clinical evidence shows a modest at best improvement in outcomes when adding antiandrogens to ADT (30). As there are additional factors, including cost and toxicity to adding antiandrogens at this stage, it remains to be seen whether this addition to chemohormonal therapy is more beneficial (31). Alternatively, antiandrogens could be combined with cabazitaxel post-chemohormonal therapy.
Whether taxanes induce cross-resistance to hormonal therapies and vice versa is also a key area of intense study and debate with major implications regarding treatment choices. Understanding therapeutic sequencing and the creation of effective combinations is paramount for future clinical success. In the current study, we see responses to both bicalutamide and enzalutamide in the AR-expressing docetaxel-resistant TaxR cells. Several preclinical and clinical studies have suggested the existence of cross-resistance between taxanes and next-generation hormonal therapies in CRPC (32, 33). It is hypothesized that inhibition of AR trafficking to the nucleus is a secondary mechanism of action for taxanes in prostate cancer, thus providing a rationale for this phenomenon (33, 34). Despite these data, others have presented findings in direct opposition, arguing against both cross-resistance between these drug classes and inhibition of AR signaling as a taxane mechanism of action (13, 35). Because it is currently unknown whether cross-resistance between drug classes is a significant clinical factor, it may be better to simply create efficacious combinations rather than wait for potential cross-resistance to develop. Our work suggests that antiandrogens can work synergistically with and may be able to prolong responses to taxanes. Thus, combination therapy may provide better outcomes than sequential use of these drugs.
In summary, we demonstrate that resistance to docetaxel confers cross-resistance to cabazitaxel and that this is mediated by increased expression of ABCB1. We also demonstrate the potential in combining antiandrogen drugs with cabazitaxel for improved efficacy.
Disclosure of Potential Conflicts of Interest
C.P. Evans has received speakers bureau honoraria from Astellas, Jansen, and Sanofi. No potential conflicts of interest were disclosed by the other authors.
Conception and design: A.P. Lombard, A.C. Gao
Development of methodology: A.P. Lombard, C. Liu, A.C. Gao
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.P. Lombard, C. Liu, C.M. Armstrong, V. Cucchiara, A.C. Gao
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.P. Lombard, C. Liu, V. Cucchiara, C.P. Evans, A.C. Gao
Writing, review, and/or revision of the manuscript: A.P. Lombard, C.M. Armstrong, A.C. Gao
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.P. Lombard, C. Liu, V. Cucchiara, X. Gu, W. Lou, A.C. Gao
Study supervision: C.P. Evans, A.C. Gao
This work was supported in part by grants NIH/NCI CA140468, CA168601, CA179970, DOD PC150229, and US Department of Veterans Affairs, ORD VA Merits I01BX0002653 (all to A.C. Gao).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Received February 23, 2017.
- Revision received May 23, 2017.
- Accepted June 20, 2017.
- ©2017 American Association for Cancer Research.