Hyperactive Notch signaling is required for the formation of Kras-mutant NSCLC.
Major finding: Hyperactive Notch signaling is required for the formation of Kras-mutant NSCLC.
Mechanism: HES1 inhibits expression of the phosphatase DUSP1, a negative regulator of ERK.
Impact: Gamma-secretase inhibitors may have therapeutic potential in NSCLC.
Notch pathway mutations have been identified in non–small cell lung cancer (NSCLC) samples, but whether Notch signaling contributes to NSCLC progression remains unclear. Given that activation of Notch pathway can be pharmacologically inhibited by γ-secretase inhibitors that are in clinical development for other diseases, Maraver and colleagues evaluated the role of Notch signaling in NSCLC to determine whether this pathway might represent a therapeutic target. Elevated levels of γ-secretase subunits, activated NOTCH1, and the effector protein hairy and enhancer of split 1 (HES1) were observed in a Kras-mutant murine NSCLC model. HES1 expression also increased with tumor stage, further suggesting that Notch pathway hyperactivation drives NSCLC progression. Genetic ablation of Notch signaling proved that this was the case, as conditional inactivation of Psen1 and Psen2, encoding the catalytic subunits of the γ-secretase complex, or Rbpj, encoding a key transcriptional mediator of the canonical Notch pathway, completely blocked the formation of Kras-mutant NSCLCs. To determine whether Notch pathway inhibition could also block the growth of established tumors, the authors treated mice harboring Kras-mutant lung adenocarcinomas with a γ-secretase inhibitor. Positron emission tomography showed that the γ-secretase inhibitor induced tumor regression, and this effect was due to Notch pathway inhibition, as HES1 levels were significantly reduced in treated tumors. Mechanistically, inhibition of HES1-mediated transcriptional suppression led to increased expression of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and negatively regulates ERK. Together with the observation that high HES1 and low DUSP1 levels are associated with poor outcome in primary human NSCLCs, these results implicate activation of the Notch pathway in NSCLC progression and provide preclinical support for the use of γ-secretase inhibitors in NSCLC.