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Published on: January 22, 2019

Caspase-8 as a Candidate Mediator Associated with Everolimus Resistance in Neuroendocrine Tumors

Cristina Grassi1,2, Miriam Bondi1,2, Giulia Albanese1

  • 1Laboratory of Translational Endocrinology and Metabolism, IRCCS Humanitas Research Hospital, Rozzano , Milan, Italy.

Journal of Molecular Endocrinology
|August 19, 2026
PubMed
Abstract

Insights

Everolimus resistance in neuroendocrine tumors (NETs) may involve caspase-8 (CASP8) upregulation. Targeting CASP8 with mTOR inhibitors could improve treatment efficacy for NET patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Everolimus, an mTORC1 inhibitor, is a key treatment for pancreatic and lung neuroendocrine tumors (NETs).
  • Acquired resistance to everolimus significantly limits its long-term effectiveness in NET patients.
  • The precise molecular mechanisms driving everolimus resistance in NETs are not fully understood.

Purpose of the Study:

  • To identify transcriptional changes associated with everolimus resistance in NET cells.
  • To investigate the role of caspase-8 (CASP8) in everolimus resistance.
  • To explore combination strategies involving CASP8 inhibition and everolimus.

Main Methods:

  • RNA sequencing of everolimus-sensitive and resistant NET cell lines.
  • Validation of differentially expressed genes using RT-qPCR in multiple NET models.
  • Pharmacological inhibition of CASP8 to assess its impact on cell viability and caspase activity.

Main Results:

  • Identified 292 dysregulated genes in resistant NET cells, including upregulation of CASP8.
  • Confirmed CASP8 upregulation as a consistent finding across different NET models.
  • CASP8 inhibition reduced NET cell viability; combined inhibition with everolimus showed the greatest effect.

Conclusions:

  • Caspase-8 (CASP8) is implicated as a mediator of everolimus resistance in NETs.
  • Alterations in extracellular matrix remodeling and receptor signaling pathways are also associated with resistance.
  • Targeting CASP8, particularly in combination with mTOR inhibitors like everolimus, represents a promising therapeutic strategy for overcoming resistance in NETs.
Keywords:
Caspase 8EverolimusNeuroendocrine tumorsResistance

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