Progetto di ricerca

AIRC: IG 2021 ID 25648 - The Aurora-A/TPX complex from mitosis to interphasic roles: novel therapeutic opportunities (DSB.AD006.348)

Area tematica

Scienze biomediche

Area progettuale

Biologia Molecolare/Cellulare (DSB.AD006)

Struttura responsabile del progetto di ricerca

Istituto di biologia e patologia molecolari (IBPM)

Responsabile di progetto

GIULIA GUARGUAGLINI
Telefono: 0649917537
E-mail: giulia.guarguaglini@uniroma1.it

Abstract

The Aurk-A kinase and its regulator TPX2 are key players in cell division. The Aurk-A/TPX2 complex, proposed as an oncogenic holoenzyme for its frequent overexpression in tumours, is emerging as a major driver of cancer and chemoresistance. Inhibition of Aurk-A mitotic functions as an anti-cancer strategy showed promising pre-clinical results but modest success in clinical trials. Recently, evidence accumulated about Aurk-A non-mitotic and kinase-independent roles in cancer cells, dependent on its nuclear localization. Aurk-A contribution to tumorigenesis may therefore not be limited to chromosomal instability deriving from aberrant mitosis.
Evidence of previously unappreciated Aurk-A kinase-independent interphasic functions raise the possibility that relevant oncogenic activities are not tackled by kinase inhibitors. Our preliminary observations suggest that TPX2, regulating mitotic Aurk-A, is also crucial to define its nuclear pool and functions. We plane to investigate nuclear Aurk-A/TPX2 regulation and activity, and their interplay with the mitotic roles, to fully understand the oncogenic functions of the complex and effectively target them for therapeutic purposes.

Obiettivi

Focusing on the Aurk-A/TPX2 interaction, we propose to (1) explore mechanisms controlling interphase nuclear localization and stability of Aurk-A; (2) assess conditions influencing unscheduled tumour-promoting Aurk-A nuclear functions; (3) investigate whether the interplay between mitotic and nuclear deregulated roles of the complex leads to tolerance to, and hence enhanced, genomic instability; (4) develop tools targeting distinct Aurk-A functions, and test their effectiveness in cancer cells with specific genetic backgrounds, in combination with drugs affecting relevant interplaying pathways.

Data inizio attività

02/01/2022

Parole chiave

Aurora-A kinase, genomic instability, cancer

Ultimo aggiornamento: 29/03/2024