RESUMO
The PI3K-AKT-mTOR pathway lies at the confluence of signaling pathways in which various components are subjected to activating genetic alterations in acute myeloid leukemia (AML), thus contributing to oncogenesis. Three AKT isoforms exist in humans. However, whether one isoform predominates in AML remains unknown. This study reveals that AKT3 behaves very distinctly than AKT1 or AKT2 in both normal myeloid differentiation and AML. During normal differentiation, AKT3 is preferentially expressed in hematopoietic stem cells whilst AKT1 becomes preferentially expressed as cells differentiate into granulocytes or monocytes. AKT2 expression remains unchanged. In AML, AKT3 expression varies widely among patient samples and is counterintuitively high in mature/monocytic leukemia. Furthermore, a low level of AKT3 expression is strongly correlated to genetic alterations associated with a better outcome (NPM1 mutations and RUNX1-RUNX1T1 translocation), while a high level is correlated to alterations associated to a bad outcome (RUNX1 mutations; and SRSF2, U2AF1, SF3B1, ASXL1 and BCOR mutations occurring frequently in MDS and MPN). Consistently, a high AKT3 expression level appears as a very strong predictor of poor survival. Curiously, although modestly varying among AML samples, a high AKT1 expression shows in contrast as a strong predictor of a better patient outcome. These data suggest that AKT3 and AKT1 expressions have strong, yet opposite, prognostic values.
Assuntos
Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-akt , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
The MAPK/ERK pathway is an essential intracellular signaling pathway. Its deregulation is involved in tumor transformation and progression. The discovery of activating mutations of BRAF in various cancers has opened new therapeutic avenues with BRAF protein kinase inhibitors. Depending on the type of cancers, these inhibitors have shown either insufficient efficacy due to primary resistance of tumor cells or transient efficacy due to the development of acquired resistance. In this review, we revisit the discoveries that led to the development of BRAF inhibitors and detail the molecular and cellular mechanisms of resistance in cancers treated with these inhibitors. Understanding these mechanisms is crucial for developing more efficient therapeutic strategies.
Title: La résistance aux inhibiteurs de BRAF - Les leçons de la clinique. Abstract: La voie de signalisation MAPK/ERK est une voie centrale de la signalisation intracellulaire. Sa dérégulation participe à la transformation et la progression tumorales. Dans plusieurs cancers, la découverte de mutations activatrices de BRAF, à l'origine de l'activation de cette voie, a ouvert de nouvelles perspectives thérapeutiques avec le développement d'inhibiteurs spécifiques de la protéine. Selon les cancers, ces inhibiteurs ont cependant montré soit une efficacité insuffisante, due à la résistance primaire des cellules tumorales, soit une efficacité transitoire, due à l'apparition d'une résistance acquise. Dans cette revue, nous revenons sur les découvertes qui ont conduit au développement de ces inhibiteurs de BRAF. Nous détaillons également les mécanismes moléculaires et cellulaires de la résistance à ces inhibiteurs observée dans différents types de cancers. Comprendre ces mécanismes est en effet primordial pour développer des stratégies thérapeutiques qui soient plus efficaces.
