ABSTRACT
Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC. This results in an imbalance in the control of E2F-dependent targets such as SPHK1, which is derepressed and drives resistance to anthracyclines in HNSCC. Specifically, we show that (i) E2F7 is subject to exportin 1 (XPO1)-dependent nuclear export, (ii) E2F7 is selectively mislocalized in most of SCC and multiple other tumor types, (iii) mislocalization of E2F7 in HNSCC causes derepression of Sphk1 and drives anthracycline resistance, and (iv) anthracycline resistance can be reversed with a clinically available inhibitor of XPO1, selinexor, in xenotransplant models of HNSCC. Thus, we have identified a strategy to repurpose anthracyclines for use in SCC. More generally, we provide a strategy to restore the balance of E2F1 (activator) and E2F7 (inhibitor) activity in cancer.
Subject(s)
Anthracyclines/pharmacology , Cell Nucleus/metabolism , Drug Resistance, Neoplasm/drug effects , E2F7 Transcription Factor/metabolism , Karyopherins/antagonists & inhibitors , Molecular Targeted Therapy , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology , Active Transport, Cell Nucleus/drug effects , Animals , Cell Line, Tumor , Cell Nucleus/drug effects , Doxorubicin/pharmacology , E2F1 Transcription Factor/metabolism , Humans , Karyopherins/metabolism , Mice, Inbred NOD , Mice, SCID , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Exportin 1 ProteinABSTRACT
BACKGROUND: Ameloblastic fibrosarcoma (AFS) is a rare odontogenic neoplasm of the jaw that usually arises de novo or through a malignant change in the mesenchymal component of a preexisting or recurrent benign fibroma. The majority of AFS cases reported in the literature arise in the mandible. CASE REPORT: A 35-year-old male presented with an asymptomatic left maxillary mass that on imaging was found to be effacing most of his maxillary sinus. He underwent a left maxillectomy with free-flap reconstruction and adjuvant radiotherapy to the tumor bed. CONCLUSION: Wide local excision remains the treatment of choice for AFS, given the poor survival rates of patients with recurrent disease. However, long-term studies and follow-up are needed to elucidate the role of adjuvant therapies in the primary treatment of AFS.