Abstract 3615: Autophagy as a drug target to prevent tumor progression in head and neck squamous cell carcinoma: Validation using a physiologically relevant mouse model
Authors: Erin E. Mowers, Mark Lingen, Ezra E.W. Cohen, Kay Macleod
Journal: Cancer Research (2015)

Abstract Squamous cell carcinoma of the head and neck (SCCHN), the sixth leading cause of cancer-related deaths worldwide, is frequently detected in its late stages, when treatment options are limited; thus, novel insight into the mechanisms underlying the development of squamous cell carcinoma and how this disease responds to drug therapies is needed to more effectively manage disease progression. Mutations in the PI3K signaling pathway are more common in SCCHN than in most other cancers. Because autophagy is a major cellular process regulated by PI3K signaling that affects response to PI3K/AKT/mTOR inhibitors, we are interested in assessing the extent to which autophagy contributes to tumor progression and drug resistance in SCCHN. With this objective in mind, we developed the first mouse model exploring the role of autophagy in the context of SCCHN using keratin 14 (K14)-driven Cre to direct deletion of Atg5-flox or Atg7-flox alleles in the oral epithelium. Unlike previous mouse models examining the role of autophagy in cancer, our physiologically relevant model does not rely on the use of strong oncogene drivers, notably KrasG12D and BrafV600E, or p53 loss; instead, the drinking water of 6- to 8-week-old mice is supplemented with 4-nitroquinoline 1-oxide (4NQO) to induce DNA damage that mimics the mutational spectrum induced by chronic tobacco and alcohol use, the most prevalent risk factors for SCCHN. Wildtype mice exposed to 4NQO develop pre-malignant lesions as well as oral squamous cell carcinoma (SCC) of the tongue within 4 to 24 weeks following 4NQO treatment that resemble human SCCHN histologically as well as molecularly. Interestingly, in wildtype mice, lesion grade is inversely correlated with expression levels of autophagic markers; for example, SCCs exhibit increased levels of p62 and loss of Atg7 and LC3. Furthermore, in normal tongue epithelium, autophagy is largely confined to the basal cell layer, and SCCs from 4NQO-treated mice continue to express the basal cell markers, K14 and p63. At 24 weeks post-cessation of 4NQO treatment, autophagy-competent mice universally exhibit dysplasia or SCC. However, autophagy-deficient K14-Cre+/-;Atg5fl/fl and K14-Cre+/-;Atg7fl/fl mice exhibit histologically normal tongues or mild hyperkeratosis, with many fewer instances of dysplasia or SCC, suggesting that early loss of autophagy prevents tumor progression to SCC. Thus, we conclude that autophagy promotes the progression of early lesions to cancers in a physiologically relevant model of SCCHN and that autophagy represents a valid target in our continuing efforts to block malignant progression of head and neck cancer. Citation Format: Erin E. Mowers, Mark Lingen, Ezra E.W. Cohen, Kay Macleod. Autophagy as a drug target to prevent tumor progression in head and neck squamous cell carcinoma: Validation using a physiologically relevant mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3615. doi:10.1158/1538-7445.AM2015-3615