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1.
Small ; 11(7): 834-43, 2015 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-25264301

RESUMO

Gold nanoparticles have garnered interest as both radiosensitzers and computed tomography (CT) contrast agents. However, the extremely high concentrations of gold required to generate CT contrast is far beyond that needed for meaningful radiosensitization, which limits their use as combined therapeutic-diagnostic (theranostic) agents. To establish a theranostic nanoplatform with well-aligned radiotherapeutic and diagnostic properties for better integration into standard radiation therapy practice, a gold- and superparamagnetic iron oxide nanoparticle (SPION)-loaded micelle (GSM) is developed. Intravenous injection of GSMs into tumor-bearing mice led to selective tumoral accumulation, enabling magnetic resonance (MR) imaging of tumor margins. Subsequent irradiation leads to a 90-day survival of 71% in GSM-treated mice, compared with 25% for irradiation-only mice. Furthermore, measurements of the GSM-enhanced MR contrast are highly predictive of tumor response. Therefore, GSMs may not only guide and enhance the efficacy of radiation therapy, but may allow patients to be managed more effectively.


Assuntos
Diagnóstico por Imagem , Nanopartículas/química , Radioterapia , Animais , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Dextranos/farmacocinética , Dextranos/farmacologia , Feminino , Ouro/farmacocinética , Ouro/farmacologia , Humanos , Estimativa de Kaplan-Meier , Nanopartículas de Magnetita , Camundongos Nus , Micelas , Polímeros/química , Radiossensibilizantes/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento
2.
Pigment Cell Melanoma Res ; 34(4): 696-702, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33000894

RESUMO

The serine-threonine kinase, BRAF, is an upstream regulator of the MEK-ERK1/2 pathway and is commonly mutated in cancer. 14-3-3 proteins bind to two sites in BRAF, N-terminal S365, and C-terminal S729. 14-3-3 binding modulates the activity and dimerization of both wild-type and non-V600 mutant forms of BRAF. In BRAF V600E mutants, the C-terminal S729 site affects dimerization of truncated splice variants. The N-terminal, S365, is removed in BRAF V600E splice variants but its importance in full-length BRAF V600 mutants remains uncertain. We tested the role of S365 in dimerization and RAF inhibitor resistance in full-length BRAF V600E. Mutating BRAF S365 site to an alanine (S365A) reduced 14-3-3 association and increased BRAF V600E homodimerization. BRAF V600E S365A displayed reduced sensitivity to RAF inhibitor at the level of MEK-ERK1/2 signaling, cell growth, and cell viability. These data suggest that alteration or removal of the S365 14-3-3 binding site may contribute to RAF inhibitor resistance.


Assuntos
Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Serina/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Indóis/farmacologia , Melanoma/genética , Melanoma/patologia , Multimerização Proteica , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia
3.
Cell Rep ; 25(6): 1501-1510.e3, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30404005

RESUMO

Expression of aberrantly spliced BRAF V600E isoforms (BRAF V600E ΔEx) mediates resistance in 13%-30% of melanoma patients progressing on RAF inhibitors. BRAF V600E ΔEx confers resistance, in part, through enhanced dimerization. Here, we uncoupled BRAF V600E ΔEx dimerization from maintenance of MEK-ERK1/2 signaling. Furthermore, we show BRAF V600E ΔEx association with its substrate, MEK, is enhanced and required for RAF inhibitor resistance. RAF inhibitor treatment increased phosphorylation at serine 729 (S729) in BRAF V600E ΔEx. Mutation of S729 to a non-phosphorylatable residue reduced BRAF V600E ΔEx-MEK interaction, reduced dimerization or oligomerization, and increased RAF inhibitor sensitivity. Conversely, mutation of the BRAF dimerization domain elicited partial effects on MEK association and RAF inhibitor sensitivity. Our data implicate BRAF S729 in resistance to RAF inhibitor and underscore the importance of substrate association with BRAF V600E ΔEx. These findings may provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Splicing de RNA/genética , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Indóis/farmacologia , Camundongos Nus , Mutação/genética , Fosforilação/efeitos dos fármacos , Multimerização Proteica , Serina/metabolismo , Especificidade por Substrato , Sulfonamidas/farmacologia , Vemurafenib/farmacologia
4.
Mol Cancer Ther ; 17(1): 84-95, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29133617

RESUMO

FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. Mol Cancer Ther; 17(1); 84-95. ©2017 AACR.


Assuntos
Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Melanoma/patologia , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia
5.
Oncotarget ; 7(20): 29689-707, 2016 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-27102439

RESUMO

Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRß. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma.


Assuntos
Comunicação Autócrina/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Melanoma/metabolismo , Receptores Proteína Tirosina Quinases/biossíntese , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos
6.
J Invest Dermatol ; 135(10): 2355-2357, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26358385

RESUMO

The novel Hsp90 inhibitor XL888 is undergoing clinical investigation for use in conjunction with the rapidly accelerated fibrosarcoma (RAF) kinase inhibitor vemurafenib to treat unresectable melanoma. The addition of XL888 to current regimens may serve an additional purpose by blocking the RAF inhibitor paradox. Such activity could reduce adverse events in patients and provide a biomarker for the successful inhibition of Hsp90 target proteins.


Assuntos
Compostos Azabicíclicos/farmacologia , Indóis/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Ácidos Ftálicos/farmacologia , Pele/efeitos dos fármacos , Sulfonamidas/farmacologia , Humanos
7.
Pigment Cell Melanoma Res ; 30(2): 177-178, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27801548
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