γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct

Abstract

Abstractγ‐Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members. Extending these findings to mammosphere inhibition assays in triple‐negative breast cancer lines, we establish that these GSIs have different functional effects. We also demonstrate that the processive γ‐secretase cleavage pattern established for amyloid precursor protein (APP) occurs in multiple substrates and that potentiation of γ‐secretase cleavage is attributable to a direct action of low concentrations of GSIs on γ‐secretase. Such data definitively demonstrate that the clinical GSIs are not biological equivalents, and provide an important framework to evaluate results from ongoing and completed human trials with these compounds.

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

“…BMS-906024 demonstrated a low nanomolar half maximal concentration (IC 50 ) in in vitro enzyme assays and cellular Notch reporter assays (20, 21). Oral administration of BMS-906024 in mice bearing T-ALL or breast cancer xenografts resulted in dose-dependent inhibition of tumor growth, with no overt toxicity observed in dosages up to 6 mg/kg (20).…”

The effect of co-treatment with DAPT and oxaliplatin on the biological behavior of human ovarian cancer stem cells

“…As such, g-secretase inhibitors inhibit the activation of Notch signaling [13,14]. As well as directly inhibiting the Notch signaling pathway in tumor cells, g-secretase inhibitors also interfere with Notch signal transduction between tumor cells and tumor vascular epithelial cells, thereby inhibiting angiogenesis [15]. DAPT is a synthetic g-secretase inhibitor that blocks the cleavage of Notch receptors, which is mediated by g-secretase.…”

Physiological functions of SPP/SPPL intramembrane proteases

“…Importantly, in cell culture models the antiviral effect of YO-01207 and LY-411575 was seen for all known genotypes of HCV and was much less susceptible to the development of drug-resistance than other antivirals, highlighting SPP-targeting small molecules as promising anti-HCV drug candidates [104]. Some GSIs including BMS-906024 and RO4929097 also potently inhibit SPPL2a and induce CD74 NTF accumulation upon application to B cells [114].…”

“…This process significantly profited from existing compounds initially generated for inhibition of the related γ-secretase for treatment of Alzheimer's disease and leukaemia [113]. While some of these inhibitors appear to selectively target γ-secretase and spare the SPP/SPPL family, others like L-685,458 and LY-411575 also inhibit processing of SPP/SPPL substrates even though with different efficiency for individual proteases [13,114,115]. In this context, it was an interesting observation that SPPL2c activity is targeted by DAPT [18], a well-established γ-secretase inhibitor (GSI) that spares all other SPP/SPPL proteases [13] strongly arguing for major differences between SPPL2c and the other family members.…”