Notably, inhibition of oncogenic NOTCH1 signaling in NOTCH1-mutated T-ALL lymphoblasts using a small set of potent γ-secretase inhibitors (GSIs) leads to cell cycle arrest and apoptosis in a manner similar to that induced by the synthetic lethal pharmacological targeting of the MYC pathway with the ABT-737 Ab and the mTOR inhibitor rapamycin.49-51 These findings put forward the idea of sectoring T-ALL therapy: while standard therapies would target the activated signaling oncogenic events, GSIs would keep the leukemic cells in a state of metabolic quiescence where the leukemic cells are particularly sensitive to the targeted effects of pharmacological inhibitors.
Biological and clinical implications. NOTCH1 is a high-affinity target for γ-secretase inhibition.52 However, no GSI has reached clinical development, likely because of its complex mechanism of action involving diverse off-target intracellular signaling pathways. Our results show that signaling and dependence on NOTCH1 can be selectively attenuated by using γ-secretase inhibitors through an off-target mechanism. The γ-secretase inhibitors, which are characterized by specific targeting of NOTCH1, show high selectivity for cancer cells containing default NOTCH1 mutations and are intrinsically toxic to cancer cells with activated receptor signaling. In addition, the γ-secretase inhibitors are cytostatic rather than cytotoxic.12 SiRNAs down-regualt NOTCH1 in a highly specific manner to within the range of the physiological distribution of NOTCH1 and, in addition, they do not need to be present clonally in cancer cells to exert their anticancer activity. Thus, they are synthetic lethal with oncogenic NOTCH1 signaling while being generally well tolerated by normal cell populations. The positive effect of NOTCH1 signaling and intracellular NOTCH1-mediated leukemic cell metabolism accounts for the variability of response to GSIs across T-ALLs, in accordance with the different levels of NOTCH1 activation seen in patients with T-ALL.12 d2c66b5586