P351: PROTEASOME INHIBITORS INDUCE DNA DAMAGE AND MITOTIC CATASTROPHE IN ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL) VIA AUTOPHAGY-MEDIATED DEGRADATION OF WEE1

Abstract

<p>ALL is an aggressive haematolymphoid malignancy and the prognosis is poor in adults with long-term survival of only 30% due to the high prevalence of high-risk subtypes. Therefore, there is an urgent need to develop novel treatment for ALL. Carfilzomib is a second-generation proteasome inhibitor which is more potent than its first-generation counterpart, bortezomib, with an excellent activity against bortezomib-resistant plasma cell myeloma. However, pre-clinical and clinical studies of carfilzomib in ALL are limited. Targeting DNA damage and mitotic defects of cancer cell is a major treatment strategy of cancer. WEE1 kinase prevents mitosis of cells with unrepaired DNA through inhibiting cyclin B. Pharmacological inhibition of WEE1 was effective in treating T-ALL with induction of DNA damage. Thus, targeting WEE1 kinase is an attractive approach of novel therapy in ALL. However, there are no studies to evaluate the mechanism of action of carfilzomib in ALL, especially in the aspect of DNA damage and mitotic catastrophe. Moreover, the role of WEE1 modulation by carfilzomib and its underlying mechanism has not been studied in ALL.<br></p>