RESUMEN
MYC proteins are major drivers of cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/química , Neuroblastoma/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Compuestos de Fenilurea/farmacología , Pirimidinas/farmacología , Regulación Alostérica , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Área Bajo la Curva , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/metabolismo , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Modelos Moleculares , Proteína Proto-Oncogénica N-Myc , Neuroblastoma/patología , Proteínas Nucleares/química , Proteínas Oncogénicas/química , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacocinética , Fosforilación , Procesamiento Proteico-Postraduccional , Estructura Secundaria de Proteína , Proteolisis , Pirimidinas/química , Pirimidinas/farmacocinética , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Relación Estructura-Actividad , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.
Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Glioma/patología , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/genética , Antineoplásicos Alquilantes/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/genética , ADN Helicasas/genética , Análisis Mutacional de ADN , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Glioma/genética , Humanos , Mutagénesis/efectos de los fármacos , Clasificación del Tumor , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genética , Temozolomida , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteína Nuclear Ligada al Cromosoma XRESUMEN
Neuroblastoma, a tumor of peripheral neural crest origin, numbers among the most common childhood cancers. Both amplification of the proto-oncogene MYCN and increased neoangiogenesis mark high-risk disease. Because angiogenesis is regulated by phosphatidylinositol 3-kinase (PI3K), we tested a clinical PI3K inhibitor, NVP-BEZ235, in MYCN-dependent neuroblastoma. NVP-BEZ235 decreased angiogenesis and improved survival in both primary human (highly pretreated recurrent MYCN-amplified orthotopic xenograft) and transgenic mouse models for MYCN-driven neuroblastoma. Using both gain- and loss-of-function approaches, we demonstrated that the antiangiogenic efficacy of NVP-BEZ235 depended critically on MYCN in vitro and in vivo. Thus, clinical PI3K/mammalian target of rapamycin inhibitors drove degradation of MYCN in tumor cells, with secondary paracrine blockade of angiogenesis. Our data demonstrated significantly improved survival in treated animals and suggest that NVP-BEZ235 should be tested in children with high-risk, MYCN-amplified neuroblastoma.