RESUMEN
Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar carcinoma (FLC) line that expresses a DNAJ-PKAc fusion and a PKA-addicted melanoma model with a mutant type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.
Asunto(s)
Carcinoma Hepatocelular , Proteínas Quinasas Dependientes de AMP Cíclico , Humanos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Carcinoma Hepatocelular/genética , Transducción de Señal , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Línea Celular TumoralRESUMEN
Hepatocellular carcinoma (HCC) constitutes 80% of all primary liver cancers. Based on key developments in the understanding of its carcinogenesis and the advancement of treatment options, detailed algorithms and practice guidelines have been published to guide the clinical management of HCC. Furthermore, several subclasses of HCC have been described based on molecular profiles and linked to pathological characteristics, clinical features, and disease aggressiveness. Most recently, the combination of the checkpoint inhibitor atezolizumab plus bevacizumab has significantly increased treatment response in the first line systemic treatment of HCC. Unfortunately, rare HCC variants, in particular fibrolamellar liver cancer (FLC), combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA), and sarcomatoid hepatocellular carcinoma (sHCC), were excluded from phase III studies. Therefore, data for decision-making and treatment allocation for these distinct entities, representing 1-5% of all primary liver cancers, is scarce. Moreover, most of the knowledge available for these rare HCC variants is based on registry data and retrospective studies. In this position paper, we briefly summarize the current clinical knowledge regarding FLC, cHCC-CCA, and sHCC. Based on our summary, we propose future clinical research activities within the framework of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER).