ONCOLOGY

Targeting TACC3 in aggressive cancers

Transforming acidic coiled-coil-containing protein 3 (TACC3) expression is highly increased in multiple different human cancers and high TACC3 levels are associated with poor prognosis (1). It is a multi-functional protein localized to microtubules, centrosomes, and nucleus. TACC3 is phosphorylated by Aurora A at Serine 558 (2). TACC3 phosphorylation is critical for binding to clathrin heavy chain (CHC) (2). TACC3 also interacts with chTOG (3). PI3KC2A acts as a scaffold protein organizing clathrin and TACC3 complex at the intermolecular bridges to crosslink the kinetochore fibers (4). TACC3 interacts with KIFC1 at the centrosomes and facilitate centrosome clustering in cancer cells bearing extra centrosomes (5). GTSE1 is an axillary member of the complex on the mitotic spindles at metaphase (6). TACC3 interacts with ARNT (HIF2A) in a hypoxia-independent manner and is necessary for transcriptional responses to hypoxia (7). TACC3 may activate the transcription of oncogenes while suppressing the transcription of tumor suppressors via interacting with HATs or NuRD complex members, MBD2 and HDAC2, respectively (5, 8). TACC3 was also recently shown to drive resistance to the iconic antibody-drug conjugate (ADC) T-DM1 in HER2-positive breast cancer (9), as well as chemoresistance in pancreatic ductal adenocarcinoma (PDAC) (10).

Literature cited:
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