Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
The chosen approach to treatment of head and neck squamous cell carcinoma (HNSCC) is a function of tumor location and stage. When indicated, multi-modality therapy comprising surgery, systemic chemotherapy, and radiotherapy may be employed to treat HNSCC. Sensitization of tumor cells to radiation has traditionally been accomplished with cytotoxic chemotherapeutic agents without regard for the underlying genetic or molecular character of the disease being treated. Ideally, sensitizing agents would be tailored to take advantage of genetic alterations uniquely found in tumor cells to minimize toxicity and maximize the therapeutic window. Recent work has demonstrated that mutations in the lysine acetyltransferases (KAT) CREBBP and EP300 found in roughly 13% of HNSCC sensitizes to radiation when combined with knockdown of the respective mutant gene. These are also bromodomain containing proteins, but targeted small molecule inhibition of the KAT activity of CREBBP and EP300 was sufficient to replicate the radiosensitizing effect of knockdown. Interestingly, the mutations observed in CREBBP HNSCC mutants produced a hyper-acetylation phenotype suggesting the mutations are activating in nature. What metabolic adaptations occur in order to fuel this hyper-acetylation phenotype are not known, raising the question of whether metabolic vulnerabilities exist that can be exploited to impose radiosensitization in a rational fashion. Using a combination of metabolomics and molecular biology, we identify alterations in glucose metabolism that occur downstream of CREBBP mutation, including increases in citrate production and glucose-derived carbon flux through tricarboxylic acid intermediates. These metabolic adaptations were found to occur without alteration in glycolytic activity. Using biguanide inhibition of mitochondrial complex I, we also demonstrate that pharmacologic inibition of electron transport in CREBBP mutant cells is sufficient to significantly sensitize these cells to radiation. These data serve to illustrate a metabolic adaptation that occurs in a subset of mutant HNSCC that may potentially be rationally radiosensitized pharmacologically using agents that disrupt mitochondrial function.