Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors

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.