Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising.

Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms

“…Intra-tumour and inter-tumour (between primary and metastatic disease) heterogeneity in the expression of SSTR2 in NENs has also been demonstrated [ 24 , 48 ]. Inter-tumour heterogeneity of SSTR2 expression is frequent, especially in metastatic deposits, as in SI metastatic NENs it is common to find that at least one of the liver lesions, especially in larger lesions, shows either low or no expression at all of SSTR2 despite the rest of the tumour burden showing SSTR2 expression [ 23 , 24 ]. The impact of heterogeneous expression of SSTR2 on the efficacy of SSAs, however, is less clear.…”

“…Gallium68 (68Ga)-DOTA-peptide positron emission tomography (PET)/CT, i.e., 68Ga-DOTATATE or 68Ga-DOTATOC, remains the gold standard for assessing the eligibility and response to peptide receptor radionuclide therapy (PRRT), especially for well-differentiated grade 1 and grade 2 GEP-NETs [ 21 , 22 ]. However, NENs often show heterogeneous expression of SSTR, which could lead to inferior outcomes following targeted treatment and subsequently influence relapse and progression of the disease [ 21 , 22 , 23 , 24 , 25 ]. High-grade lesions and metastases can have a lower expression of SSTRs which may not be fully assessed on receptor-based imaging alone.…”