ESTRO 2020 Abstract Book

S247 ESTRO 2020

OC-0447 ATP Citrate Lyase is associated with radiosensitivity in head and neck squamous cell carcinoma E. Göttgens 1 , C. Van den Heuvel 2 , M. De Jong 3 , J. Kaanders 1 , W. Leenders 2 , M. Ansems 1 , J. Bussink 1 , P. Span 1 1 Radboud university medical center, Radiotherapy and OncoImmunology Laboratory- Department of Radiation Oncology, Nijmegen, The Netherlands ; 2 Radboud university medical center, Department of Biochemistry, Nijmegen, The Netherlands ; 3 The Netherlands Cancer Institute, Department of Radiation Oncology, Amsterdam, The Netherlands Purpose or Objective Radiotherapy is an important treatment modality of head and neck squamous cell carcinomas (HNSCC). Tumour metabolism might influence radiosensitivity, and a relationship between metabolism and clinical outcome has been reported. Here we probed a large number of genes involved in metabolism for their role in radiosensitivity both in vitro and in patient cohorts. Material and Methods Radiosensitivity of 14 human HNSCC cell lines was determined using colony forming assays and the expression profiles of approximately 200 metabolic and targetable tyrosine kinase genes were generated using targeted RNA sequencing by single molecule Molecular Inversion Probes. The effect of pharmacological inhibition of candidate genes on DNA repair (53BP1 foci and homologous recombination assays) and radiosensitivity (colony forming assays) was established in vitro. The predictive value was assessed in patients in silico (n=445) and validated in a separate cohort (n=91). The subcellular localisation was established using immunohistochemistry in HNSCCs and also related to outcome. Results Correlation between radiosensitivity data and expression profiles yielded 18 genes associated with radiosensitivity or -resistance. Pharmacological inhibition of ATP citrate lyase (ACLY) ACLY caused an impairment of DNA damage repair, specifically homologous recombination (HR), and lead to radiosensitisation in several HNSCC cell lines. This did not occur after inhibition of fatty acid synthase (FASN), suggesting that ACLY inhibited HR via histone acetylation as reported earlier (1). In silico examination of a TCGA cohort of HNSCC patients revealed that high expression ACLY was predictive for radiotherapy response, as it was only associated with poor overall survival in patients who received radiotherapy (hazard ratio (HR) = 2.00, 95% CI: 1.12 – 3.55; P = 0.0184). These data were further validated in an independent cohort of HNSCC patients treated with chemoradiation (HR = 4.17; 95% CI 1.35-12.86; P = 0.0130). Furthermore, patients with poor locoregional control after radiotherapy has significantly higher nuclear ACLY protein levels, again in line with its reputed role in attenuating HR via histone acetylation.

Figure: patients with poor locoregional control (locoregional event within 8 months) had significantly higher levels of ACLY in the nucleus (left, P = 0.037). In patients with good locoregional control (no event within 3 years after primary treatment), ACLY was almost unequivocally expressed in the cytoplasm, but not the nucleus (right). Conclusion ACLY affects DNA damage repair, and is a predictive factor for radiotherapy treatment outcome in HNSCC. Patients treated with (chemo)irradiation may benefit from pharmacological inhibition of ACLY. OC-0448 Epigenetic regulation and cellular plasticity in response to irradiation in head and neck cancer C. Peitzsch 1,2,3 , S.I. Schniewind 1 , F. Schwarz 1,3,4 , S. Richter 5 , A. Linge 1,2,3,6 , S. Löck 1,3,6 , W.W. Hadiwikarta 7 , A. Nowrouzi 7,8 , M. Baumann 6,7 , M. Krause 1,2,3,4,6 , A. Dubrovska 1,3,4 , I. Kurth 7 1 OncoRay - Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus- Technische Universität Dresden, Dresden, Germany ; 2 National Center for Tumor Diseases NCT, German Cancer Research Center DKFZ- Heidelberg, Dresden, Germany ; 3 German Cancer Consortium DKTK- partner site Dresden, German Cancer Research Center DKFZ- Heidelberg, Dresden, Germany ; 4 Institute of Radiooncology-OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany ; 5 Institute of Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus- Technische Universität Dresden, Dresden, Germany ; 6 Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus- Technische Universität Dresden, Dresden, Germany ; 7 German Cancer Research Center DKFZ, dkfz, Heidelberg, Germany ; 8 Heidelberg Institute for Radiation Oncology HIRO, Heidelberg University Hospital, Heidelberg, Germany Purpose or Objective Within tumors, the cancer stem cell (CSC) population is characterized by enhanced self-renewal, differentiation potential, and migratory capacity. Therefore, CSCs are thought to be responsible for tumor growth, therapy resistance, and metastasis initiation. Novel findings indicating that CSCs undergoing phenotypical and functional adaptations during tumorigenesis, upon microenvironmental changes and under therapeutic pressure. Despite radiotherapy (RT) has the potential to 1. Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination. Mol Cell, 2017. 67 (2): p. 252-265 e6.