RESUMEN
The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. VIDEO ABSTRACT.
Asunto(s)
Receptores ErbB/metabolismo , Neoplasias Faciales/tratamiento farmacológico , Neoplasias Faciales/veterinaria , Proteómica/métodos , Factor de Transcripción STAT3/metabolismo , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Animales , Metilación de ADN , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias Faciales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antígenos de Histocompatibilidad Clase I/metabolismo , Marsupiales , Ratones , Fosforilación , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4-130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4-130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Furthermore, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. Overall, the synergistic effects of AC-4-130 with TK inhibitors (TKIs) as well as emerging treatment strategies provide new therapeutic opportunities for leukemia and potentially other cancers.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Factor de Transcripción STAT5/antagonistas & inhibidores , Animales , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Leucemia Mieloide Aguda/genética , Nitrilos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas , Terpenos/farmacología , Tirosina Quinasa 3 Similar a fmsRESUMEN
The conjugate alkynylation of alkylidene Meldrum's acids with alkynylalanes and alkynyl Grignards allows for the formation of propargylic all-carbon quaternary stereocenters in high yields. Ag2CO3-catalyzed intramolecular cyclization of propargylic Meldrum's acid derivatives offers a two-step entry into complex γ-alkylidene butyrolactones containing an all-carbon quaternary center at the C-4 position.