Endocrine Abstracts

Introduction: Neuroendocrine tumors of the lung (BP-NETs) are fairly rare tumors with very heterogeneous behavior and molecular characteristics. They are very heterogeneous concerning their malignancy, ranging from slow proliferating carcinoids (typical (TC) and atypical carcinoids (ATC)) to very aggressive large cell neuroendocrine carcinomas (LCNEC) and small cell lung cancers (SCLC). For the highly proliferative BP-NETs, combined chemotherapy is the standard therapy option, whereas for the lung carcinoids, Everolimus has recently been assessed in the Radiant-4 study as moderately effective concerning time to progression. Nevertheless the treatment options are limited and unsatisfactory. The cell cycle and DNA damage response (DDR) regulator FOXM1 has been lately demonstrated to be associated with grading in BP-NETs tumor biopsies and to be targetable by proteasome inhibition in vitro.

Purpose: The experimental (RNAi) and pharmacological (bortezomib) inhibition of FOXM1 was studied to assess the chemo-sensitizing effect of targeting FOXM1.

Material and methods: TC, ATC, large-cell NEC, small-cell NEC and a NSCLC cell line were treated with siRNA against FOXM1 or bortezomib, cisplatin or a combination of cisplatin and either siRNA or bortezomib versus controls. The efficacy and molecular effects were studied by proliferation analysis, western blot, flow cytometry and multiplexed gene expression analysis (Nanostring technologies).

Results: In TP53 wildtype carcinoids, knockdown of FOXM1 induced an enhanced induction of apoptosis and reduced mitosis after cisplatin therapy versus controls. Bortezomib, which shows several additional effects on DDR, strongly induced G2 arrest and reduction of mitosis in the cell lines. When combined with cisplatin, the G2 arrest turned into increased induction of apoptosis in the majority of the cell lines.

Conclusion: Targeting FOXM1 and Bortezomib treatment enhance the effect of cisplatin-chemotherapy in BP-NET in vitro.