RESUMEN
Cell cycle dysregulation, characterised by aberrant activation of cyclin dependent kinases (CDKs), is a hallmark of cancer. After years of research on the first and second generations of less selective CDK inhibitors with unfavourable clinical activity and toxicity profiles, CDK4/6 inhibitors become the first and only class of highly specific CDK inhibitors being approved for cancer treatment to date. CDK4/6 inhibitors have transformed the treatment paradigm of estrogen receptor-positive (ER+) breast cancer, dramatically improving the survival outcomes of these patients when incorporated with conventional endocrine therapies in both the first and later-line settings. Currently, the efficacies of CDK4/6 inhibitors in other breast cancer subtypes and cancers are being actively explored. All three CDK4/6 inhibitors have demonstrated very similar clinical efficacies. However, being the least similar structurally, abemaciclib is the only CDK4/6 inhibitor with single agent activity in refractory metastatic ER + breast cancer, the ability to cross the blood brain barrier efficiently, and a distinct toxicity profile of lower myelosuppression such that it can be dosed continuously. Here, we further discuss the distinguishing features of abemaciclib as compared to the other two CDK4/6 inhibitors, palbociclib and ribociclib. Besides being the most potent inhibitor of CDK4/6, abemaciclib exhibits a wider selectivity towards other CDKs and kinases, and functions through additional mechanisms of action besides inducing G1 cell cycle arrest, in a dose dependent manner. Hence, abemaciclib has the potential to act independently of the CDK4/6-cyclin D-RB pathway, resulting in crucial implications on the possibly expanded clinical indications and predictive biomarkers of abemaciclib, in contrast to the other CDK4/6 inhibitors. The current status of preclinical evidence and clinical studies of abemaciclib as a single agent and in combination treatment in breast and other cancers, together with its potential predictive biomarkers, is also summarised in this review.
Asunto(s)
Aminopiridinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Proliferación Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Aminopiridinas/efectos adversos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/efectos adversos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Transducción de Señal , Resultado del TratamientoRESUMEN
Bcl-2 agonist of cell death (BAD) is a BH3-only member of the Bcl-2 family which possesses important regulatory function in apoptosis. BAD has also been shown to possess many non-apoptotic functions closely linked to cancer including regulation of glycolysis, autophagy, cell cycle progression and immune system development. Interestingly, BAD can be either pro-apoptotic or pro-survival depending on the phosphorylation state of three specific serine residues (human S75, S99 and S118). Expression of BAD and BAD phosphorylation patterns have been shown to influence tumor initiation and progression and play a predictive role in disease prognosis, drug response and chemosensitivity in various cancers. This review aims to summarize the current evidence on the functional role of BAD phosphorylation in human cancer and evaluate the potential utility of modulating BAD phosphorylation in cancer.