Aurora Kinase A Is Overexpressed in Human Retinoblastoma and Correlates with Histopathologic High-Risk Factors: Implications for Targeted Therapy

Abstract

Retinoblastoma (RB) is an intraocular malignancy initiated by loss of RB1 function and/or dysregulation of MYCN oncogene. RB is primarily treated with chemotherapy; however, systemic toxicity and long-term side effects remain a significant challenge necessitating the identification of specific molecular targets. Aurora kinase A (AURKA), a critical cell cycle regulator, contributes to cancer pathogenesis especially in RB1-deficient and MYCN dysregulated tumors. Our immunohistochemistry study in patient specimens (n=67) discovered that AURKA is overexpressed in RB and elevated expression correlates with one or more histopathological high-risk factors such as tumor involvement of the optic nerve, choroid, sclera and/or anterior segment. More specifically, AURKA is ubiquitously expressed in majority of the advanced-stage RB tumors that show a sub-optimal response to chemotherapy. shRNA-mediated depletion/pharmacological inhibition studies in cell lines, patient-derived cells, in-vivo xenografts, and enucleated patient specimens confirm that RB cells are highly sensitive to a lack of functional AURKA. In addition, we deciphered that AURKA and MYCN associate with each other to regulate their levels in RB cells. Overall, our results demonstrate a previously unknown upregulation of AURKA in RB, facilitated by its crosstalk with MYCN, and elevated levels of this kinase may indicate unfavorable prognosis in tumors refractory to chemotherapy. This study provides a rationale and confirms that therapeutic targeting of elevated AURKA in RB could be a potential treatment approach.