Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogenous group of malignancies originating from neuroendocrine cells of the gastrointestinal tract, the incidence of which has been increasing for several decades. While there has been significant progress in the development of therapeutic options for patients with advanced or metastatic disease, these remain limited both in quantity and durability of benefit. This review examines the latest research elucidating the mechanisms of both up-front resistance and the eventual development of resistance to the primary systemic therapeutic options including somatostatin analogues, peptide receptor radionuclide therapy with lutetium Lu 177 dotatate, everolimus, sunitinib, and temozolomide-based chemotherapy. Further, potential strategies for overcoming these mechanisms of resistance are reviewed in addition to a comprehensive review of ongoing and planned clinical trials addressing this important challenge.

Keywords: chemotherapy; gastroenteropancreatic neuroendocrine tumors; neuroendocrine tumors; peptide receptor radionuclide therapy; resistance; somatostatin receptor; targeted therapies.

Figure 1

Classification and grading criteria for neuroendocrine neoplasms of the gastrointestinal tract as per 2019 World Health Organization criteria. On H&E and IHC staining, NETs (well-differentiated) demonstrate preserved organoid pattern and infrequent mitotic activity while NECs (poorly differentiated) demonstrate loss of organoid morphology, necrosis, and typically high levels of mitotic activity. On imaging, increasing tumor grade frequently demonstrates an inverse correlation with SSTR-directed PET activity and a direct correlation with FDG-PET activity. Abrreviations: NET neuroendocrine tumor; NEC neuroenocrine carcinoma, H&E hematoxylin and eosin; PET positron emission tomography, FDG fluorodeoxyglucose.

Figure 2

Mechanism of action for commonly utilized therapies for the treatment of GEP-NETs. Described mechanisms of treatment resistance are denoted by red arrows with specific resistance mechanism to each therapeutic class denoted by a corresponding numbered red circle. Abbreviations: SSTR somatostatin receptor, PRRT peptide receptor radionuclide therapy, mTOR mammalian target of rapamycin, TKI tyrosine kinase inhibitor, VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; KIT stem cell growth factor receptor, TKR tyrosine kinase receptor, BMSC bone marrow-derived stem cells.