Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines
© Lopez-Acevedo et al.; licensee BioMed Central Ltd. 2014
Received: 22 March 2014
Accepted: 2 July 2014
Published: 30 September 2014
To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway.
SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated.
Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine-docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1.
Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted.
KeywordsDasatinib Leiomyosarcoma SRC pathway Targeted agents Uterine sarcoma
Leiomyosarcomas (LMS) are a rare and aggressive type of uterine malignancy that has an extremely poor prognosis. Uterine sarcomas represent only 3-9% of all uterine malignancies and LMS account for 40% of all uterine sarcomas [1, 2]. Even in the setting of early-stage disease 53 to 71% of women will develop recurrences that are often extra-pelvic and incurable. The prognosis is dismal with a historical progression-free survival rate at 2 years (PFS2 yrs) of only 30% for patients treated with surgery alone .
Chemotherapy with a combination of gemcitabine and docetaxel has shown the most promise to date. The overall response rate has ranged from 42% to 53% with a median duration of response of greater than 7 months in women with unresectable LMS . Most recently, adjuvant gemcitabine and docetaxel was evaluated in women with completely resected stage I to IV uterine LMS. The PFS2 yrs was 45% with a median PFS of 13 months and the median survival was not yet reached . Despite these modest improvements, there is an urgent need for innovative therapeutic approaches.
One novel and promising therapeutic agent is dasatinib (BMS-354825) (NSC 732517). Dasatinib is a potent, orally-bioavailable, small molecule inhibitor that has been shown to inhibit at least five protein tyrosine kinases/kinase families: SRC family kinases, BCR-ABL, c-KIT, EPHA2 and the PDGFβ receptor [5, 6]. SRC kinase interacts with a variety of receptor tyrosine kinases such as EGFR, PDGFR, and c-KIT as well as other cellular factors such as focal adhesion kinase (FAK). These pathways are integral components of cellular function and regulate cellular migration, proliferation, survival, angiogenesis, and metastasis. The SRC pathway and its substrates (FAK) as well as c-KIT, EGFR and PDGF tyrosine kinase receptors have been found to be overexpressed in a wide variety of sarcomas including LMS [7–9]. Most recently, Shank et al. showed that EGFR, VEGF and c-KIT is expressed in uterine LMS specimens . In particular, 57% of uterine LMS specimens express c-KIT.
Given the activity of gemcitabine and docetaxel as well as the pre-clinical data regarding the SRC pathway in LMS, we sought to explore the activity of dasatinib (a SRC inhibitor) in combination with these cytotoxic agents in uLMS.
Gemcitabine and docetaxel were purchased from Sigma (St. Louis, MO). Dasatinib (BMS-354825) was provided by Bristol-Myers-Squibb (Princeton, NJ) via the National Cancer Institute (NCI). Dasatinib, gemcitabine and docetaxel were dissolved in dimethylsulfoxide (DMSO). Concentrated stock solutions of all drugs were stored at -25°C.
SK-UT-1 and SK-UT-1B cell lines were obtained from the American Type Culture Collection (Manassas, VA). SK-UT-1 and SK-UT-1B cell lines are uterine in origin. Cell lines were grown and maintained in monolayer culture in RPMI 1640 (Gibco) media supplemented with 10% fetal bovine serum (Hyclone, Logan UT), 1% sodium pyruvate, 100 units/ml penicillin, 100 ug/ml stremptomycin and 1% nonessential amino acids in a humidified chamber containing 5% CO2.
Meso scale discovery (MSD) analysis
MSD analysis was performed for SRC and paxillin. Paxillin is a SRC pathway substrate that is phosphorylated by SRC and FAK upon integrin binding or growth factor stimulation. Cells were seeded at 3×106 cells per plate of each cell line, and allowed to reach confluence over 24 hours. Cells were incubated at 37°C for 24 hours with dasatinib at a escalating concentrations of 30, 100 and 500 nmol/L. Controls were treated with DMSO. Anti-total Src antibody (tSrc) (Cell Signaling Technology, Inc., Danvers, MA, Cat#2108), anti-pSrc pY418 antibody (Invitrogen, Carlsbad, CA, Cat# 44660G), anti-total paxillin antibody (Cell Signaling Technology, Inc., Danvers, MA, Cat#2542), or anti-phospho paxillin (Tyr118) antibody (Cell Signaling Technology, Inc., Danvers, MA, Cat#2541) were added at 1ug/ml to bare, goat anti-mouse plates (MSD, Gaithersburg MD), and incubated at room temperature (R.T.) for 1 hour. The plates were washed with TBS/ 0.05% Tween-20 three times and protein lysate from SK-UT-1 (20 ug total protein) or SK-UT-1B (20 ug total protein) cells were added and incubated for 2 hours at R.T. Sulfo-TAG (MSD, Cat#R91AN-1) labeled anti-Src antibody (R&D, Cat# AF3389) were then added to the plates and incubated for 1 hour at room temperature after plates were washed. The plates were imaged and analyzed using a MSD Sector Imager 2400 and associated software. The electroluminescence value was normalized to each control and plotted as a percent of control. Statistical analysis was performed using two-tailed unpaired t-test.
Cell proliferation assay
Tumor cells were seeded at a density of 2,500 cells/well in a 96-well plate, and allowed to reach 70% confluence over 24 hours. Cells were then incubated with each drug at 37°C for 72 hours with escalating doses: docetaxel (0.1 nmol/L-1000 nmol/L), gemcitabine (0.1 nmol/L-100 nmol/L) and dasatinib (10 nmol-4000 nmol/L). Control wells contained RPMI media only. All experiments were done using exponentially proliferating cells. After the 72 hours drug incubation period, 5 μl of ATP luminescence solution was added to each well and cell proliferation was measured by ATP content using the Luminescence ATP cell detection assay system according to manufacturer’s recommendations. Experiments to determine the IC50 were performed in triplicate.
The percentage of growth inhibition was calculated using the following: survival ratio = # live cellstreated group /#live cellscontrol group × 100. The half maximal inhibitory concentration (IC50) was defined as the drug concentration at which the 50% of the cell growth was inhibited and was analyzed using GraphPad Prism software (version 4.03 San Diego, CA). Single-agent dose response curves were constructed and the IC50 for gemcitabine and docetaxel was computed from the best fitting transition functions (determined by F-statistic). The average IC50 of all experiments performed was chosen as the final IC50. Given the lack of significant activity of dasatinib as a single-agent, the IC25 was calculated from the dose response curve. The cells were subsequently treated with combinations of gemcitabine and docetaxel; dasatinib and gemcitabine; dasatinib and docetaxel; and the three-drug simultaneous and sequential combination of gemcitabine, docetaxel, and dasatinib. For gemcitabine and docetaxel, fixed-ratio molar concentrations ranging from 0.125 to 4 multiples of the single-drug IC50 was used. Dasatinib was added at a fixed 1:1 ratio using the IC25.
Two-drug combination effect evaluation and statistical methodologies
The IC50 obtained for single-agent gemcitabine and docetaxel was compared to the IC50 calculated for each cytotoxic agent after adding dasatinib IC25. To analyze the drug interaction between both cytotoxic agents and dasatinib combined with either agent, the coefficient of drug interaction (CDI) was calculated. CDI is defined by the following formula; CDI = AB/(A × B) [10, 11]. According to the absorbance of the luminescence of each group, AB is the ratio of the two-drug combination group to the control group, and A or B is the ratio of the single drug group to the control group. CDI < 1 indicates synergism, CDI < 0.7 significant synergism, CDI = 1 additivity and CD > 1 antagonism . Due to the lack of significant activity of dasatinib and the inability to obtain an IC50 for this agent, the CDI formula was utilized to evaluate the anti-proliferative effect between dasatinib and each cytotoxic agent. This formula permits calculation of drug-to-drug interaction without a requisite IC50. All experiments were performed in duplicate.
Triple drug simultaneous and sequential combination effect evaluation and statistical methodologies
where D is the dose that yields x% growth inhibition and α = 0 for mutually exclusive drugs (the drugs have similar sites of action). Combination index scale was defined as: CI <0.9 synergistic, CI = 0.9-1.1 additive, CI = 1.1-1.2 slight antagonism, CI = 1.2-1.45 moderate antagonism, CI = 1.45-3.3 antagonism, CI = 3.3-10 strong antagonism.
In contrast to the two-drug combination where the CDI formula was used, the median effect (CI formula) method was utilized to evaluate triple-drug interaction. This was possible because both gemcitabine and docetaxel reached an IC50 as single agents. For sequencing studies, drug exposures were separated by 24 hours. The combination index between gemcitabine and docetaxel was computed with and without the addition of dasatinib IC25. All experiments were performed in triplicate.
Meso scale discovery (MSD) analysis
SRC protein expression
In SK-UT-1B, there was a loss of SRC activation at 30 nm (11%, p < 0.001), 100 nm (11%, p < 0.001) and 500 nm (5%, p < 0.001) compared to controls (Figure 1). There was a decrease in pSRC levels after treatment with single-agent dasatinib at 30 nm (17%, p < 0.001), 100 nm (7%, p < 0.001) and 500 nm (4%, p < 0.001) and an increase in tSRC after treatment with single-agent dasatinib at 30 nm (152%, p < 0.001), but a decrease at 100 nm (64%, p < 0.001) and 500 nm (74%, p < 0.001) (Additional file 2: Figure S2 and Additional file 3: Figure S3).
Paxillin protein expression
Anti-proliferative activity of single-agent gemcitabine, docetaxel and dasatinib
IC 50 of each cytotoxic agent alone and in combination with dasatinib (IC 25 ) and coefficient of drug interaction (CDI)
4.02 (SD ± 1.0)
4.30 (SD ± 0.5)
2.35 (SD ± 1.4)
1.15 (SD ± 0.07)
2.97 (SD ± 0.5)
0.94 (SD ± 0.6)
0.85 (SD ± 0.6)
0.52 (SD ± 0.4)
Drug interaction assessment for combination dasatinib and cytotoxic chemotherapy
The combination index (CI) in uterine LMS cell lines
Combination index (CI) at the IC 50
Gemcitabine + Docetaxel + Dasatinib
Dasatinib- > Gemcitabine + Docetaxel
Gemcitabine + Docetaxel- > Dasatinib
Dasatinib + Gemcitabine- > Docetaxel
Dasatinib + Docetaxel- > Gemcitabine
Gemcitabine- > Docetaxel + Dasatinib
Docetaxel- > Gemcitabine + Dasatinib
Gemcitabine + Docetaxel + Dasatinib
Dasatinib- > Gemcitabine + Docetaxel
Gemcitabine + Docetaxel- > Dasatinib
Dasatinib + Gemcitabine- > Docetaxel
Dasatinib + Docetaxel- > Gemcitabine
Gemcitabine- > Docetaxel + Dasatinib
Docetaxel- > Gemcitabine + Dasatinib
Discussion and conclusion
Dasatinib has not been shown to be a potent agent when used alone in a variety of solid tumors . Schrage et al. previously reported their findings of dasatinib in chondrosarcoma cell lines . The maximum percent of growth inhibition in the chondrosarcoma cell lines was approximately 50%. They also explored dasatinib’s effect on SRC phosphorylation and caspase-3- mediated apoptosis. Although dasatinib treatment of chondrosarcoma decreased SRC phosphorylation, indicating target inhibition, it did not result in an increase in apoptosis. Therefore, the inhibition of SRC and its family of kinases was not sufficient to promote cell death. In a large clinical trial of patients with incurable sarcoma, which included 47 participants with LMS, dasatinib did not have a significant anti-tumor activity as a single agent . Based on pre-clinical and clinical data, it appears that single agent dasatinib does not have significant clinical activity in soft tissue sarcomas.
However, our pre-clinical study investigating the activity of dasatinib in combination with gemcitabine and docetaxel in uterine LMS demonstrates that dasatinib acts synergistically with gemcitabine or docetaxel in a two-drug combination and in select triplet combinations in the analyzed uterine LMS cell lines. Our findings in sequential and triple combination yielded conflicting results. Interestingly, the simultaneous triple-drug combination of dasatinib IC25, gemcitabine and docetaxel in SK-UT-1 yielded a synergistic effect, although the magnitude of that effect is probably minimal (CI = 0.59 to 0.46). Conversely, the gemcitabine and docetaxel doublet demonstrated an antagonistic effect in SK-UT-1B cells and that effect was not reversed with the addition of dasabinib in the simultaneous triple-drug combination. However, in select sequencing experiments, dasatinib enhanced the anti-proliferative effect of gemcitabine and docetaxel; gemcitabine + docetaxel + dasatinib; dasatinib followed by docetaxel + gemcitabine; and gemcitabine followed by docetaxel + dasatinib. In the latter two experiments, this finding may be due to avoidance of the antagonistic interaction of the gemcitabine and docetaxel doublet in the SK-UT-1B cell line as well as partially attributed to the synergistic effect of the dasatinib doublet. The results with the sequential dasatinib followed by combination gemcitabine and docetaxel indicate a possible role for priming with dasatinib.
We hypothesize that our synergistic findings may in part be due to the inhibition of the SRC pathway. Our MSD analysis revealed that dasatinib inhibited the SRC pathway based on reduction of pSRC and p-paxillin protein expression and ratios pSRC/tSRC and p-paxcillin/t-paxillin. Even at very low doses of dasatinib (30 nM), the SRC pathway was inhibited in both uLMS cell lines. This suggests that an optimal biologic effect on SRC can occur with low doses of dasatinib. However, expression of paxillin was only inhibited at high doses. A possible explanation for this is that downstream substrates of SRC pathway may be activated via different pathways. The SRC pathway is a complex pathway with convergent and divergent interactions. It is not clear that the anti-proliferative effect we noted in our study was a direct result of inhibition of the SRC pathway. Most recently, Shank et al. showed that EGFR, VEGF and especially c-KIT were expressed in uterine LMS specimens . In particular, 57% of uterine LMS specimens expressed c-KIT. Therefore, dasatinib’s anti-proliferative effect seen in our study may be via the inhibition of the c-KIT pathway in addition to or instead of inhibition of the SRC pathway.
Another important property of dasatinib not related to cytotoxicity, lies in its ability to inhibit migration and cell invasion. Dasatinib has been shown to inhibit cell migration in non-small cell lung cancer, head and neck squamous cell cancer, neuroblastoma, and multiple soft tissue and bone sarcoma cell lines [8, 17, 18]. Johnson and colleagues reported that the anti-migratory effects of dasatinib were present regardless of the effects seen on proliferation and survival . In addition, Shor et al. showed that dasatinib significantly inhibited cellular invasion using matrigel invasion chambers. With the exception of one rhabdomyosarcoma cell line, the IC50 dose to inhibit cell migration and invasion in the soft tissue sarcoma cell lines ranged from 4-65 nmol/L and was similar to the IC50 dose (range 3 nmol/L to 68 nmol/L) to inhibit SRC phosphorylation . This finding suggests that SRC inhibition may be responsible for suppression of sarcoma cellular migration and invasion. The universal effects seen on migration and invasion suggest that beneficial clinical effects may be achieved without direct cancer cell cytotoxicity and provides a possible role of dasatinib in preventing metastasis. Inhibition of metastasis is especially important in aggressive tumors such as LMS which are known to rapidly spread to distant sites.
While we and others have reported synergistic and additive effects with dasatinib and a variety of chemotherapeutic agents in preclinical studies of ovarian and breast cancer cell lines and ovarian cancer xenografts [19–21], the clinical activity of dasatinib either alone or in combination with cytotoxic agents in solid tumors has been disappointing. In a phase I trial of dasatinib in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer, the triplet combination demonstrated clinical activity but was also associated with a higher than expected rate of hematologic toxicity. Pharmacokinetic analysis showed that concurrent administration of dasatinib with paclitaxel did not significantly alter either dasatinib or paclitaxel drug concentrations . Two randomized studies of another SRC inhibitor, saracatinib, with chemotherapy in ovarian cancer demonstrated no improvement in response rate or survival, but higher toxicity [22, 23]. Therefore, the addition of dasatinib to chemotherapy is unlikely to be beneficial in an unselected patient population and there is a need to identify biomarkers that can be used to direct therapy. Of note, these studies used the maximum tolerated dose (MTD). In our data, we observed an increased antiproliferative effect of dasatinib in combination with cytotoxic agents at a minimal active dose. Hence, combination effects may be beneficial at lower doses of dasatinib in the treatment of uterine leiomyosarcoma.
Up-regulation of the SRC pathway has been shown to be associated with resistance to cytotoxic therapy. In mucinous ovarian cancer cell lines, Matsuo et al. revealed that treatment with oxaliplatin induced phosphorylation of SRC kinase and this contributed to the chemoresistance observed in this tumor. This induced activity was subsequently inhibited by concurrent administration of dasatinib, which resulted in a synergistic anti-tumor effect .
To our knowledge, there are no clinical trials that have evaluated the toxicity of gemcitabine and docetaxel in combination with dasatinib. In a prospective trial of women with completely resected uterine leiomyosarcoma, treatment with gemcitabine plus docetaxel was generally well-tolerated. Potential serious toxicities associated with gemcitabine plus docetaxel in the advanced disease setting included pulmonary toxicity and myelosuppression requiring administration of granulocyte-colony stimulating factor . Based on our prior experience, we anticipate that the addition of dasatinib to gemcitabine and docetaxel would be associated with even greater hematologic toxicity. A phase I evaluation would be required to determine if biologically relevant doses could be delivered with the triplet combination. However, the disparate sequential combination results in our cell lines was not expected and requires further study. Alternatively, doublet therapy with dasatinib plus gemcitabine or docetaxel may be more effective than triplet therapy.
We acknowledge the limitations of our study, which include the use of only two LMS cell lines rather than primary tumor, and the use of in vitro models. Further investigation in in vivo models is warranted to confirm our in vitro results. Further study is also needed to determine if dasatinib exerts its function via inhibition of the SRC pathway or via other tyrosine kinases, such as BCR-ABL, c-KIT, EPHA2, EGFR and PDGF, or a combination. In summary, we are the first to report an anti-proliferative effect of dasatinib in combination with cytotoxic agents in uterine leiomyosarcoma.
We thank the Charles Hammond Research Fund and the Sandra H. Barbeau Foundation for granting financial assistance to conduct this project the National Cancer Institute for providing the cytotoxic agents.
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