Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

• Molecular response to chemo-, radio- and radionuclide therapy was assessed in NENs. Cisplatin PRRT triggered DNA damage repair-related gene expression. Bortezomib inhibited repair related Combined resulted short-term pro-apoptotic effects vitro . Tumoral heterogeneity interfered with long-term sensitization assessment vivo Background: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors a slow proliferation. They virtually resistant many DNA-damaging therapeutic approaches, such as chemo- external beam therapy, which might be overcome by inhibition induced proteasome inhibitors bortezomib. Methods results: In this study, we several combined treatment modalities By cell-based functional analyses, 3D ovo an orthotopic mouse model, demonstrated sensitizing of bortezomib cisplatin, radiation peptide receptor (PRRT). expression profiling western blot, explored the underlying mechanisms, impaired repair. Therapy-induced extrinsic proapoptotic signaling well induction cell cycle arrest, leading decreased vital tumor volume altered tissue composition shown magnetic resonance imaging F-18-FDG-PET , however no significant additional benefit alone. Conclusions: We that has when damaging interfering Nevertheless, due high after observations, were not able prove advantage bortezomib-combined model.