Fig. 9. Graphical model for therapeutic inhibition of Notch and PKC in T-ALL cells to prevent drug resistance.

a In sensitive cells, NOTCHi leads to downregulation of its transcriptional target cMyc, which in turn regulates S6 phosphorylation in a mTORC1-dependent manner. b After chronic administration of Notch inhibitors, cells adapt to Notch absence through the upregulation of PKCδ, which phosphorylates S6 and sustains cMyc expression in a Notch-independent manner. c Notch and PKCδ activation show a mutually exclusive pattern. In fact, PKC inhibition by sotrastaurin leads to upregulation of cMyc expression. d The combined inhibition of Notch and PKC has a synergistic effect and fully inhibits the development of acquired resistance.