TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

Abstract

Genomic instability is a hallmark feature of cancer cells, and can be caused by defective DNA repair, for instance due to inactivation of BRCA2. Paradoxically, loss of Brca2 in mice results in embryonic lethality, whereas cancer cells can tolerate BRCA2 loss. This holds true for multiple DNA repair genes, and suggests that cancer cells are molecularly "rewired" to cope with defective DNA repair and the resulting high levels of genomic instability. In this study, we aim to identify genes that genomically unstable cancer cells rely on for their survival. Using functional genomic mRNA (FGmRNA) profiling, 16,172 cancer samples were previously ranked based on their degree of genomic instability. We analyzed the top 250 genes that showed a positive correlation between FGmRNA levels and the degree of genomic instability, in a co-functionality network. Within this co-functionality network, a strong cluster of 11 cell cycle-related genes was identified, including TPX2. We then assessed the dependency on these 11 genes in the context of survival of genomically unstable cancer cells, induced by BRCA2 inactivation. Depletion of TPX2 or its associated kinase Aurora-A preferentially reduced cell viability in a panel of BRCA2-deficient cancer cells. In line with these findings, BRCA2-depleted and BRCA2-mutant human cell lines, or tumor cell lines derived from Brca2;p53 mice showed increased sensitivity to the Aurora-A kinase inhibitor alisertib, with delayed mitotic progression and frequent mitotic failure. Our findings reveal that BRCA2-deficient cancer cells show enhanced sensitivity to inactivation of TPX2 or its partner Aurora-A, which points at an actionable dependency of genomically unstable cancers.

Excess TPX2 Interferes with Microtubule Disassembly and Nuclei Reformation at Mitotic Exit

“…We report that TPX2 overexpression induces a strong delay of mitotic progression at the level of prometaphase, associated with aberrant spindle structure, as also shown in transformed cells [21,24,46]. This is, at least in part, independent of the TPX2/Aurora-A interaction, since mitotic delay, as well as spindle abnormalities, were observed in both the TPX2 FL -and the TPX2 ∆43 -overexpressing cultures; still, TPX2 FL overexpression was significantly more efficient in inducing spindle organisation defects.…”

“…Similar results were obtained in a mouse model, where lack of TPX2 induced early embryonic lethality and TPX2-deficient mouse embryonic fibroblasts transiently arrested in prometaphase with abnormally assembled spindles and less stable K-fibres, and eventually exited mitosis without chromosome segregation [23]. Experiments in human tumour cells showed that TPX2 overexpression also affects spindle assembly [21,24]. Several tumours overexpress TPX2 [2,[25][26][27], often within signatures of mitotic genes, frequently including Aurora-A [25,28,29].…”

Identification of potential biomarkers in subtypes of epithelial ovarian cancer

“…Several studies demonstrate that TPX2 is overexpressed in multiple cancer types and play important role in promoting tumorigenesis and metastasis (Liang et al, 2016;Zou et al, 2018). A recent study reported that TPX2/AURK signaling as potential target in genomic unstable cancer cell including ovarian cancer and breast cancer (Hsu et al, 2017;van Gijn et al, 2019).…”

“…UBE2C (Ubiquitin-conjugating enzyme E2C) protein is involved in the ubiquitination process that modifies the abnormal or short-lived proteins with ubiquitin and target toward degradation (van Wijk et al, 2010). A good number of studies showed high expression of UBE2C is associated with aggressive progression and poor outcomes of several cancer (Dastsooz et al, 2019).…”

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

“…TPX2 has been shown to contribute to survival in ovarian 28 and endometrial 29 cancers. Cancer cells with increased genetic instability also show increased sensitivity to suppression of TPX2 30 . Our data demonstrate a novel role of TPX2 in HR in EAC.…”