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?-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct.

ABSTRACT: ?-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 ?-secretase cleavage pattern established for amyloid precursor protein (APP) occurs in multiple substrates and that potentiation of ?-secretase cleavage is attributable to a direct action of low concentrations of GSIs on ?-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.

SUBMITTER: Ran Y

PROVIDER: S-EPMC5494507 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Ran Yong Y Hossain Fokhrul F Pannuti Antonio A Lessard Christian B CB Ladd Gabriela Z GZ Jung Joo In JI Minter Lisa M LM Osborne Barbara A BA Miele Lucio L Golde Todd E TE

EMBO molecular medicine 20170701 7

γ-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 ...[more]

PMID: 28539479

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Project description:Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. IMPLICATIONS FOR PRACTICE: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.

Project description:The NOTCH1 gene encodes a transmembrane receptor protein with activating mutations observed in many T-cell acute lymphoblastic leukemias (T-ALLs) and lymphomas, as well as in other tumor types, which has led to interest in inhibiting NOTCH1 signaling as a therapeutic target in cancer. Several classes of Notch inhibitors have been developed, including monoclonal antibodies against NOTCH receptors or ligands, decoys, blocking peptides, and ?-secretase inhibitors (GSIs). GSIs block a critical proteolytic step in NOTCH activation and are the most widely studied. Current treatments with GSIs have not successfully passed clinical trials because of side effects that limit the maximum tolerable dose. Multiple ?-secretase-cleavage substrates may be involved in carcinogenesis, indicating that there may be other targets for GSIs. Resistance mechanisms may include PTEN inactivation, mutations involving FBXW7, or constitutive MYC expression conferring independence from NOTCH1 inactivation. Recent studies have suggested that selective targeting ?-secretase may offer an improved efficacy and toxicity profile over the effects caused by broad-spectrum GSIs. Understanding the mechanism of GSI-induced cell death and the ability to accurately identify patients based on the activity of the pathway will improve the response to GSI and support further investigation of such compounds for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL. IMPLICATIONS FOR PRACTICE: ?-secretase has been proposed as a therapeutic target in numerous human conditions, including cancer. A better understanding of the structure and function of the ?-secretase inhibitor (GSI) would help to develop safe and effective ?-secretase-based therapies. The ability to accurately identify patients based on the activity of the pathway could improve the response to GSI therapy for the treatment of cancer. Toward these ends, this study focused on ?-secretase inhibitors as a potential therapeutic target for the design of anti-NOTCH1 therapies for the treatment of T-cell acute lymphoblastic leukemias and lymphomas.

Dataset Information

?-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct.

Publications

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

Similar Datasets

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