Chapter 26 - Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is an aggressive, recurrent neoplasm that is characterized by poor prognosis and low overall survival. EGFR has been found to be associated with HNSCC, and cetuximab is the first anti-EGFR antibody approved for use in HNSCC. Despite the efficacy of cetuximab, most patients will relapse due to acquired resistance. The Hedgehog signaling pathway (HhP) is also frequently active in HNSCC and has been reported to integrate with EGFR signaling to induce tumorigenesis and drug resistance. In this chapter, researchers describe a study that found that long-term exposure to EGFR inhibition upregulated the HhP transcription factor GLI1 in HNSCC cells as they developed resistance to cetuximab. Conversely, inhibition of HhP enhanced the dependence of EGFR in HNSCC cells and therefore delayed or blocked tumor recurrence when used together with cetuximab. Moreover, the combination of cetuximab and the HhP inhibitor IPI-296 has a more pronounced antitumor effect than cetuximab monotherapy in HNSCC patient-derived xenografts. Together, these findings suggest that HhP inhibitors have the potential to sensitize HNSCC to anti-EGFR therapy. A phase I clinical trial (NCT01255800) found that the combinatorial therapy appears to be tolerable and showed signs of efficacy for HNSCC.