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Lung cancer is the leading cause of cancer-related deaths among men and women. γ-Secretase inhibitors, a class of small-molecule compounds that target the Notch pathway, have been tested to treat non-small-cell lung cancer (NSCLC) in preclinical and clinical trials. Although γ-secretase inhibitors elicit a response in some tumors as single agents and sensitize NSCLC to cytotoxic and targeted therapies, they have not yet been approved for NSCLC therapy. We discuss our recently published preclinical study using the γ-secretase inhibitor AL101, formerly BMS906024, on cell lines and PDX models of NSCLC, primarily lung adenocarcinoma. We propose that Notch pathway mutations may not be the most suitable biomarker for predicting NSCLC response to γ-secretase inhibitors. γ-Secretases have over 100 known γ-secretase cleavage substrates. Many of the γ-secretase substrates are directly involved in carcinogenesis or tumor progression, and are ideal candidates to be the "on-target" biomarkers for γ-secretase inhibitors. We propose the need to systematically test the γ-secretase and other targets as potential biomarkers for sensitivity before continuing clinical trials. Now that we have entered the postgenome/transcriptome era, this goal is easily attainable. Discovery of the biomarker(s) that predict sensitivity to γ-secretase inhibitors would guide selection of the responder population that is most likely to benefit and move the compounds closer to approval for therapeutic use in NSCLC.

Rethinking Gamma-secretase Inhibitors for Treatment of Non–small-Cell Lung Cancer: Is Notch the Target?