Atonal Homolog 1 Is Required for Growth and Differentiation Effects of Notch/γ-Secretase Inhibitors on Normal and Cancerous Intestinal Epithelial Cells

ATOH1 is required for all effects of GSIs in intestinal crypts and adenomas; Notch has no unique function in intestinal progenitors and cancer cells other than to regulate ATOH1 expression. Reducing ATOH1 activity might mitigate intestinal toxicity from systemic GSI therapy for nonintestinal diseases. Among gastrointestinal malignancies, ATOH1 mediates the effects of GSIs, so ATOH1 expression levels might predict responses to these inhibitors. We propose that only the subset of CRCs that retain ATOH1 expression will respond to GSIs.