Growth inhibitory effect of rapamycin in Hodgkin-lymphoma cell lines characterized by constitutive NOTCH1 activation

Growing evidence identified deregulation of signalling elements of Notch and mammalian target of rapamycin (mTOR) pathways. These signals play important roles in cellular functions and malignancies. Their tumorigenic role in T-cell acute lymphoblastic leukaemia (T-ALL) are well known, however, their potential interactions and functions are poorly characterized in Hodgkin lymphoma (HL). The aim of our study was to characterize the mTOR and Notch signalling elements in HL cell lines (DEV, L1236, KMH2) and human biopsies, furthermore to investigate influencing effects of these signalling in tumour growth. High mTOR activity and constitutive NOTCH1 activation were confirmed in the studied cell lines without any known oncogenic mutations, especially the elements of both pathways. The anti-tumour effect of Notch inhibitors are well known in some preclinical models but the resistance and side effects are evinced in many cases. mTOR and Notch inhibitor treatments and their combination were tested in gamma-secretase inhibitor (GSI) resistant HL cells in vitro and in vivo. The mTOR inhibitor and its combination treatments could reduce the tumour growth, furthermore it was more effective in xenograft models in vivo. Based on these results constitutively activated NOTCH1 could be a potential target in HL therapy and mTOR inhibitors could be suggested as effective agents to decrease tumour growth in the case of Notch inhibitor resistance