Resistance of neuroendocrine tumours to somatostatin analogs.

Introduction: A common feature shared by most neuroendocrine tumors (NETs) is the expression on their surface of somatostatin receptors (SSTRs) that are essential for their pathophysiological regulation, diagnosis, and management. The first-generation synthetic somatostatin analogs (SSAs), octreotide and lanreotide, constitute the cornerstone of treatment for growth hormone secreting pituitary adenomas and functioning, progressive functioning, and non-functioning gastro-entero-pancreatic (GEP-NETs). SSAs exert their mechanism of action through binding to the SSTRs; however, their therapeutic response is frequently attenuated or diminished by the development of resistance. The phenomenon of resistance is complex implicating the presence of additional epigenetic and genetic mechanisms.

Areas covered: We aim to analyze the molecular, genetic, and epigenetic mechanisms of resistance to SSA treatment. We also summarize recent clinical data related to the development of resistance on conventional and non-conventional modes of administration of the first-generation SSAs and the second-generation SSA pasireotide. We explore mechanisms used to counteract the resistance to SSAs using higher doses or more frequent mode of administration of SSAs and/or combination treatments.

Expert opinion: There is considerable heterogeneity in the development of resistance to SSAs that is tumor-specific necessitating the delineation of the underlying pathophysiological processes to further expand their therapeutic applications.