septiembre14Referencia

Cancer Res. 2014 Feb 15;74(4):1190-9. doi: 10.1158/0008-5472.CAN-13-1750.

Autores

Barceló C, Paco N, Morell M, Alvarez-Moya B, Bota-Rabassedas N, Jaumot M, Vilardell F, Capella G, Agell N.

Resumen

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors.

Descripción

Si bien el KRAS oncogénico es potencialmente una buena diana terapéutica, la obtención de fármacos que bloqueen su actividad ha resultado de momento infructuosa. En este trabajo se demuestra como la modificación postraduccional del KRAS oncogénico por fosforilación en la Ser181 es necesaria para el crecimiento tumoral a través de la activación de dos de sus principales efectores AKT y ERK. Además, se ha encontrado dicha modificación en tumores humanos de adenocarcinoma ductal de páncreas. En conjunto, nuestrosdatos sugieren la utilización de inhibidores de la fosforilación de KRAS como estrategia terapéuticaen tumores con KRAS mutado.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo liderado por la Dra. Neus Agell tiene como objetivo general analizar los mecanismos de transducción de señales que regulan el ciclo celular así como la implicación de sus alteraciones en la oncogénesis. En los últimos años se ha centrado las siguientes líneas de investigación: regulación de la funcionalidad de KRAS por unión a calmodulina y por fosforilación; y, mecanismos reguladores de los checkpoints de replicación y de daño al DNA y sus alteraciones en células tumorales.

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