ABSTRACT
BACKGROUND: Addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapy significantly increased progression-free survival, leading to their approval and incorporation into the metastatic breast cancer treatment paradigm. With these inhibitors being routinely used for patients with advanced estrogen receptor-positive (ER+) breast cancer, resistance to these agents and its impact on subsequent therapy needs to be understood. Considering the central role of ER in driving the growth of ER+ breast cancers, and thus endocrine agents being a mainstay in the treatment paradigm, the effects of prior CDK4/6i exposure on ER signaling and the relevance of ER-targeted therapy are important to investigate. The objective of this study was to evaluate the anti-tumor activity of elacestrant, a novel oral selective estrogen receptor degrader (SERD), in preclinical models of CDK4/6i resistance. METHODS: Elacestrant was evaluated as a single agent, and in combination with alpelisib or everolimus, in multiple in vitro models and patient-derived xenografts that represent acquired and "de novo" CDK4/6i resistance. RESULTS: Elacestrant demonstrated growth inhibition in cells resistant to all three approved CDK4/6i (palbociclib, abemaciclib, ribociclib) in both ESR1 wild-type and mutant backgrounds. Furthermore, we demonstrated that elacestrant, as a single agent and in combination, inhibited growth of patient-derived xenografts that have been derived from a patient previously treated with a CDK4/6i or exhibit de novo resistance to CDK4/6i. While the resistant lines demonstrate distinct alterations in cell cycle modulators, this did not affect elacestrant's anti-tumor activity. In fact, we observe that elacestrant downregulates several key cell cycle players and halts cell cycle progression in vitro and in vivo. CONCLUSIONS: We demonstrate that breast cancer tumor cells continue to rely on ER signaling to drive tumor growth despite exposure to CDK4/6i inhibitors. Importantly, elacestrant can inhibit this ER-dependent growth despite previously reported mechanisms of CDK4/6i resistance observed such as Rb loss, CDK6 overexpression, upregulated cyclinE1 and E2F1, among others. These data provide a scientific rationale for the evaluation of elacestrant in a post-CDK4/6i patient population. Additionally, elacestrant may also serve as an endocrine backbone for rational combinations to combat resistance.
Subject(s)
Breast Neoplasms/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/pharmacology , Receptors, Estrogen/metabolism , Tetrahydronaphthalenes/pharmacology , Animals , Antineoplastic Agents , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Female , Humans , Mice , Models, Biological , Molecular Targeted Therapy , Xenograft Model Antitumor AssaysABSTRACT
El concepto de traslado neonatal es antiguo, pero recientemente ha tomado fuerza mundialmente, existiendo países totalmente organizados. En Chile se ha comenzado a realizar la actualización de este proceso. El Hospital San Borja Arriar n clasifica el riesgo del neonato para el traslado según características y problemas de salud. Esto junto a la norma ministerial fue la base para cumplir el propósito de evaluar el grado de cumplimiento de la norma en los traslados neonatales realizados en la unidad de Neonatología del Hospital Doctor Sótero del Río. En este estudio cuantitativo descriptivo, prospectivo, transveral se aplicó una pauta de cotejo mediante la observación a traslados en Bajo, Mediano y Alto Riesgo y luego se determinó el grado de cumplimiento de los pasos sugeridos por la norma del Ministerio de Salud. La muestra conformada por 45 traslados, corresponde principalmente a neonatos de pretérmino, mayores de 7 días, peso superior a 2500 grs. y enfermedad no quirúrgica. Los traslados de la unidad son principalmente de bajo riesgo (f33), destaca que un 60 por ciento de éstos no cumplen adecuadamente la norma por falta de control de signos vitales del neonato durante el traslado y de registro del procedimiento. En los traslados de mediano riesgo (f7) se observó un 71 por ciento de incumplimiento de la norma, se suma a los factores antes mencionados la ejecución por personal inadecuado
