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Investigating intrinsic radiosensitivity biomarkers to peptide receptor radionuclide therapy with [177Lu]Lu-DOTATATE in a panel of cancer cell lines

par Delbart, Wendy ;Ghanem, Ghanem Elias ;Karfis, Ioannis ;Flamen, Patrick ;Wimana, Zéna
Référence Nuclear medicine and biology, 96-97, page (68-79)
Publication Publié, 2021-05-01

Article révisé par les pairs

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Résumé :

Introduction: [177Lu]Lu-DOTATATE is an effective systemic targeted radionuclide therapy for somatostatin receptor (SSTR) positive metastatic or inoperable neuroendocrine tumours (NET). However, for a given injected activity, tumour responses are variable. Our aim was to investigate whether SSTR expression/functionality and known characteristics of intrinsic radiosensitivity, namely proliferation rate, glucose metabolism, cell cycle phase, DNA repair and antioxidant defences were predictors of sensitivity to [177Lu]Lu-DOTATATE in SSTR expressing human cancer cell lines. Methods: In six human cancer cell lines and under basal condition, SSTR expression was assessed by qRT-PCR and immunocytochemistry. Its functionality was evaluated by binding/uptake assays with [68Ga]Ga- and [177Lu]Lu-DOTATATE. The radiosensitivity parameters were evaluated as follows: proliferation rate (cell counting), glucose metabolism ([18F]FDG uptake), antioxidant defences (qRT-PCR, colorimetric assay, flow cytometry), DNA repair (qRT-PCR) and cell cycle (flow cytometry). Effect of [177Lu]Lu-DOTATATE on cell viability was assessed 3, 7 and 10 days after 4 h incubation with [177Lu]Lu-DOTATATE using crystal violet. Results: Based on cell survival at day 10, cell lines were classified into two groups of sensitivity to [177Lu]Lu-DOTATATE. One group with <20% of survival decrease (−14 to −1%) and one group with >20% of survival decrease (−22 to −33%) compared to the untreated control cell lines. The latter had significantly lower total antioxidant capacity, glutathione (GSH) levels and glucose metabolism (p < 0.05) compared to the first group. SSTR (p = 0.64), proliferation rate (p = 0.74), cell cycle phase (p = 0.55), DNA repair (p > 0.22), combined catalase and GSH peroxidase expression (p = 0.42) and superoxide dismutase (SOD) activity (p = 0.41) were not significantly different between the two groups. Conclusion: Antioxidant defences may be major determinants in [177Lu]Lu-DOTATATE radiosensitivity.