Interactions of Multitargeted Kinase Inhibitors and Nucleoside Drugs: Achilles Heel of Combination Therapy?

Damaraju, Vijaya L.; Kuzma, Michelle; Mowles, Delores; Cass, Carol E.; Sawyer, Michael B.

doi:10.1158/1535-7163.mct-14-0337

Cited by 20 publications

(11 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that at the doses administered, ponatinib did not enhance the effect of this combination therapy in vivo . The absence of synergy of ponatinib with gemcitabine and cisplatin may be due to the relatively high dose of gemcitabine and cisplatin we administered; or alternatively, could be due to the recently demonstrated ability of many tyrosine kinase inhibitors to block accumulation of co-administered gemcitabine in cancer cells, rendering the combination less effective [36]. As the combination of gemcitabine (50 mg/kg) and cisplatin (2.5 mg/kg) almost completely inhibited tumor growth, it was difficult to achieve an additional effect by combination with ponatinib.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

et al. 2016

View full text Add to dashboard Cite

Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.

show abstract

Section: Discussionmentioning

confidence: 99%

Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

et al. 2016

View full text Add to dashboard Cite

show abstract

“…A clinical regimen of PTX/Gem combination approved for the first-line treatment of metastatic pancreatic cancer recommends sequential administration of PTX followed by Gem [120]. In some cases, simultaneous delivery or reverse-order delivery may induce additive or even antagonistic effects [121–123]. Moreover, there have been clinical cases where simultaneous chemotherapy combination causes greater toxicity than sequentially-administered drugs with no significant advantages in overall survival time [124].…”

Section: Sequential Deliverymentioning

confidence: 99%

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

Meng¹,

Han²,

Yeo³

2016

Expert Opinion on Drug Delivery

View full text Add to dashboard Cite

Introduction Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug. Areas covered We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic- or photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control. Expert opinion Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery.

show abstract

“…For this reason, ENT1 has been postulated to be an emergent transporter of clinical importance, that has to be studied during the development of new molecular entities with nucleoside-like structures according to the International Transporter Consortium [ 15 ]. In this context, it is noteworthy that various tyrosine kinase inhibitors (TKIs), such as the bcr-abl inhibitors nilotinib, ponatinib, bosutinib, dasatinib, and imatinib, the EGF receptor inhibitors erlotinib and gefitinib, and the multi-kinase inhibitors axitinib, pazopanib, sunitinib, and vandetanib, have been shown to inhibit ENT1 activity in vitro [ 16 – 19 ]. Whether other TKIs can also behave as inhibitors for ENT1 is, however, unknown, but likely deserves interest owing to the current development of TKIs as a leading pharmacological class for various therapeutic indications, and to the potential co-administration of nucleoside analogues and TKIs, notably for the treatment of cancers.…”

Section: Introductionmentioning

confidence: 99%

Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors

Jouan

Moreau

Bruyère

et al. 2021

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

Background and Objectives Equilibrative nucleoside transporter (ENT) 1 is a widely-expressed drug transporter, handling nucleoside analogues as well as endogenous nucleosides. ENT1 has been postulated to be inhibited by some marketed tyrosine kinase inhibitors (TKIs). To obtain insights into this point, the interactions of 24 TKIs with ENT1 activity have been analyzed. Methods Inhibition of ENT1 activity was investigated in vitro through quantifying the decrease of [ 3 H]-uridine uptake caused by TKIs in HAP1 ENT2-knockout cells, exhibiting selective ENT1 expression. TKI effects towards ENT1-mediated transport were additionally characterized in terms of their in vivo relevance and of their relationship to TKI molecular descriptors. Putative transport of the TKI lorlatinib by ENT1/ENT2 was analyzed by LC-MS/MS. Results Of 24 TKIs, 12 of them, each used at 10 µM, were found to behave as moderate or strong inhibitors of ENT1, i.e., they decreased ENT1 activity by at least 35%. This inhibition was concentration-dependent for at least the strongest ones (IC 50 less than 10 µM) and was correlated with some molecular descriptors, especially with atom-type E-state indices. Lorlatinib was notably a potent in vitro inhibitor of ENT1/ENT2 (IC 50 values around 1.0-2.5 µM) and was predicted to inhibit these nucleoside transporters at relevant clinical concentrations, without, however, being a substrate for them. Conclusion Our data unambiguously add ENT1 to the list of drug transporters inhibited by TKIs, especially by lorlatinib. This point likely merits attention in terms of possible drug-drug interactions, notably for nucleoside analogues, whose ENT1-mediated uptake into their target cells may be hampered by co-administrated TKIs such as lorlatinib.

show abstract

Interactions of Multitargeted Kinase Inhibitors and Nucleoside Drugs: Achilles Heel of Combination Therapy?

Abstract: Multitargeted tyrosine kinase inhibitors (TKI) axitinib, pazopanib, and sunitinib are used to treat many solid tumors.

Cited by 20 publications

References 55 publications

Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors

Contact Info

Product

Resources

About