Presenter(s)
S. Thoidingjam1, S. Sriramulu1, A. Haider Muratoglu1, S. L. Brown2, O. Hassan1, B. Movsas2, H. Ali3, S. Chang4, P. Ha5, F. Siddiqui2, and S. Nyati1; 1Henry Ford Health, Detroit, MI, 2Department of Radiation Oncology, Henry Ford Health, Detroit, MI, 3Department of Medical Oncology, Henry Ford Cancer Institute, Detroit, MI, 4Department of Otolaryngology, Henry Ford Cancer Institute, Detroit, MI, 5University of California, San Francisco, San Francisco, CA
Purpose/Objective(s): Adenoid Cystic Carcinoma (ACC) is a rare and lethal type of head and neck cancer. Standard therapy involves surgery followed by radiation therapy. The role of chemotherapy, including targeted therapy, is investigational. The majority of ACC have MYB overexpression and MYB-NFIB gene fusions, while Notch mutations are associated with aggressive behavior. Targeted therapies against these drivers or their downstream targets have been incompletely explored, especially in combination with radiotherapy of ACC.
Materials/Methods: Genomic and survival analyses were conducted using ACC tumor datasets from cBioPortal. Expression of MYB, AKT, ATR, NOTCH and NFIB was assessed via RNA-seq, qRT-PCR, and western blot in ACC tumors, PDX models, and cell lines. ACC cells (UM-HACC-2A) and normal cells were treated with targeted inhibitors alone or in combination with ionizing radiation (IR). DNA damage and repair were analyzed using ?H2AX and RAD51 foci assays, while qPCR was used to assess cell death via apoptosis assays.
Results: We observed that MYB, ATR, AKT1, Notch1, Notch2 and NFIB are overexpressed in ACC tumors, PDX (RNAseq), and cell lines (qRTPCR, western blots). ACC patients with alterations in ATR, AKT, MYB and NFIB have poorer overall survival (OS) compared to subjects with no alterations. ATR, AKT and Notch inhibitors sensitized UM-HACC2A cells to radiation without significantly affecting normal cells. Target engagement experiments showed that drugs combined with ionizing radiation (IR) reduced the expression (mRNA) of their respective targets. ?H2AX and RAD51 foci assays confirmed that the DNA double-strand break (DSB) response and the homologous recombination (HR) repair pathway were affected by the combination treatment.
Conclusion: Our results confirmed overexpression of MYB, ATR, AKT, Notch1, Notch2 and NFIB in ACC, and demonstrated that ATR, AKT and Notch inhibitors radiosensitize a preclinical model of ACC (unpublished data; confidential).