Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms.

Notch signaling is a highly conserved pathway important for normal embryonic development and as well as cancer. We previously demonstrated a role for Notch3 in lung cancer pathogenesis. Notch3 inhibition resulted in tumor apoptosis and growth suppression. In vitro, these effects were enhanced when the EGFR pathway was also inhibited, suggesting significant crosstalk between these two pathways. How Notch3 and EGFR/MAPK pathways cooperate in modulating apoptosis is not yet known. In this study, we provide evidence that Notch3 regulates Bim, a BH-3-only protein via MAPK signaling. Furthermore, loss of Bim expression prevents tumor apoptosis induced by Notch3 inhibition. Using γ-secretase inhibitor and erlotinib in a xenograft model, Bim induction and tumor inhibition were enhanced compared to either agent alone, consistent with our previous observation of significant synergism between Notch and EGFR/ras/MAPK signaling. Thus, our data support the hypothesis that Notch3 not only plays a crucial role in lung cancer through regulating apoptosis but also cooperates with the EGFR/MAPK pathway in modulating Bim.