1. ¹Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA
2. ²Department of Medicine, Dartmouth Medical School, Hanover, NH, USA
3. ³Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
4. ⁴Department of Pathology, Dartmouth Medical School, Hanover, NH, USA
5. ⁵Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH, USA
6. ⁶Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

Correspondence: Dr DJ Robbins, Department of Pharmacology and Toxicology, Dartmouth Medical School, 7650 Remsen, Remsen 607, Hanover, NH 3755, USA. E-mail: david.j.robbins@dartmouth.edu

Received 3 February 2006; Revised 13 June 2006; Accepted 17 June 2006; Published online 14 August 2006.

Abstract

Although it had previously been suggested that the hedgehog (HH) pathway might be activated in some lung tumors, the dependence of non-small cell lung carcinomas (NSCLC) for HH activity had not been comprehensively studied. During a screen of a panel of 60 human tumor cell lines with an HH antagonist, we observed that the proliferation of a subset of NSCLC cell lines was inhibited. These NSCLC cell lines express HH, as well as key HH target genes, consistent with them being activated through an autocrine mechanism. Interestingly, we also identified a number of NSCLC cell lines that express high levels of the downstream transcription factor GLI1 and harbor enhanced levels of HH activity, but appear insensitive to known HH antagonists. We hypothesized that the high levels of GLI1 in these cells would function downstream of the HH antagonist target, allowing them to bypass the antagonist-mediated block in proliferation. Consistent with this hypothesis, when the levels of GLI1 are knocked down in such cells, they become sensitive to these inhibitors. We go on to show that a large percentage of primary NSCLC samples express GLI1, consistent with constitutive activation of the HH pathway in these samples. Taken together, these results establish the involvement of the HH signaling pathway in a subset of NSCLCs.