Bcr-Abl tyrosine kinase inhibitors significantly improved Philadelphia chromosome-positive leukaemia therapy. Apart from Bcr-Abl kinase, imatinib, dasatinib, nilotinib, bosutinib and ponatinib are known to have additional off-target effects that might contribute to their antitumoural activities. In our study, we identified aldo-keto reductase 1B10 (AKR1B10) as a novel target for dasatinib. The enzyme AKR1B10 is upregulated in several cancers and influences the metabolism of chemotherapy drugs, including anthracyclines. AKR1B10 reduces anthracyclines to alcohol metabolites that show less antineoplastic properties and tend to accumulate in cardiac tissue. In our experiments, clinically achievable concentrations of dasatinib selectively inhibited AKR1B10 both in experiments with recombinant enzyme (Ki = 0.6 µM) and in a cellular model (IC50 = 0.5 µM). Subsequently, the ability of dasatinib to attenuate AKR1B10-mediated daunorubicin (Daun) resistance was determined in AKR1B10-overexpressing cells. We have demonstrated that dasatinib can synergize with Daun in human cancer cells and enhance its therapeutic effectiveness. Taken together, our results provide new information on how dasatinib may act beyond targeting Bcr-Abl kinase, which may help to design new chemotherapy regimens, including those with anthracyclines.
- Klíčová slova
- Anthracyclines, Cancer therapy, Leukaemia, Multidrug resistance, Reductase,
- MeSH
- aldo-keto reduktasy antagonisté a inhibitory chemie metabolismus MeSH
- bcr-abl fúzní proteiny antagonisté a inhibitory chemie metabolismus MeSH
- buňky A549 MeSH
- chemorezistence účinky léků fyziologie MeSH
- dasatinib aplikace a dávkování MeSH
- daunomycin aplikace a dávkování MeSH
- HCT116 buňky MeSH
- inhibitory proteinkinas aplikace a dávkování MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- protinádorové látky aplikace a dávkování MeSH
- sekundární struktura proteinů MeSH
- simulace molekulového dockingu MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- AKR1B10 protein, human MeSH Prohlížeč
- aldo-keto reduktasy MeSH
- bcr-abl fúzní proteiny MeSH
- dasatinib MeSH
- daunomycin MeSH
- inhibitory proteinkinas MeSH
- protinádorové látky MeSH
The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2-LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556-67. ©2018 AACR.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- buněčné jádro účinky léků MeSH
- cholangiokarcinom farmakoterapie genetika patologie MeSH
- cytoplazma účinky léků MeSH
- dasatinib aplikace a dávkování MeSH
- fosfoproteiny genetika MeSH
- fosforylace účinky léků MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protein-serin-threoninkinasy genetika MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- signální proteiny YAP MeSH
- signální transdukce účinky léků MeSH
- skupina kinas odvozených od src-genu antagonisté a inhibitory genetika MeSH
- transkripční faktory MeSH
- tyrosin genetika MeSH
- tyrosinkinasa p56(lck), specifická pro lymfocyty genetika MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- dasatinib MeSH
- fosfoproteiny MeSH
- LATS1 protein, human MeSH Prohlížeč
- LCK protein, human MeSH Prohlížeč
- protein-serin-threoninkinasy MeSH
- signální proteiny YAP MeSH
- skupina kinas odvozených od src-genu MeSH
- transkripční faktory MeSH
- tyrosin MeSH
- tyrosinkinasa p56(lck), specifická pro lymfocyty MeSH
- YAP1 protein, human MeSH Prohlížeč
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. PATIENTS AND METHODS: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. RESULTS: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. CONCLUSIONS: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.
- Klíčová slova
- anticancer therapy, dasatinib, gemcitabine, pancreatic cancer,
- MeSH
- dasatinib aplikace a dávkování MeSH
- deoxycytidin aplikace a dávkování analogy a deriváty MeSH
- dospělí MeSH
- duktální karcinom slinivky břišní farmakoterapie mortalita patologie MeSH
- dvojitá slepá metoda MeSH
- gemcitabin MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory slinivky břišní farmakoterapie mortalita patologie MeSH
- proporcionální rizikové modely MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- dasatinib MeSH
- deoxycytidin MeSH
- gemcitabin MeSH
