Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Abstract

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

Von Hippel-Lindau Syndrome: Medical Syndrome or Surgical Syndrome? A Surgical Perspective

“…Recently, studies were investigated on belzutifan, development code: MK-6482, which is a hypoxia-inducible factor-2α (HIF-2α) inhibitor for the treatment of adult patients with Hippel-Lindau syndrome. This agent is not FDA approved in US and had a 83% response rate in PNETs (37)(38)(39).…”

Case report: composite pancreatic intraductal papillary mucinous neoplasm and neuroendocrine tumor: a new mixed neuroendocrine-non-neuroendocrine neoplasm?

“…Combining the results, KRAS mutation might be an important diver mutation of composite IPMN-NET. Since the status of KRAS have been studied in pure IPMN and NEN in multiple studies, we further searched COSMIC database for the information of the other two mutated genes ( PCK1 and MLL3 ) in pancreatic neoplasms (Table 2 ) [ 46 – 48 ]. We found that most PCK1 mutations occur in pancreatic ductal adenocarcinoma (several samples with unknown histology subtype).…”

Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies

“…The prognosis in patients with advanced pancreatic neuroendocrine neoplasms (panNENs) has been generally poor and, until recently, there has been little improvement, mainly due to the lack of new therapeutic approaches which have led to effective anti-tumor treatment activity in these patients [ 7 , 9 , 11 , 12 , 13 , 14 , 15 ]. In the past decade, however, there has been significant advances, not only in the treatment approaches for panNEN patients with advanced disease, the recognition into the pathogenesis of the acquired and primary resistance to anti-tumor treatment which is an increasing problem, but also in the diagnosis, management and overall treatment of panNENs, as well as other NENs, which is beginning to influence survival rates in these patients [ 7 , 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. We have recently analyzed both these advances and controversies in identifying prognostic factors for the overall management of panNEN patients, as well as for surgical outcomes [ 7 ].…”

“…Despite these recent advances, resistance to anti-tumor therapies, either primary resistance or acquired resistance, in patients with advanced PanNENs, is an increasing problem [ 6 , 20 , 21 , 29 , 75 , 76 , 77 , 78 , 79 ]. This is a similar finding to its occurrence with similar anti-tumor treatments in patients with other non-NEN advanced malignancies [ 80 ], as well as patients with advanced NENs in other non-pancreatic locations (i.e., carcinoids) [ 6 , 29 , 76 , 77 , 78 , 79 ].…”

“…This is a similar finding to its occurrence with similar anti-tumor treatments in patients with other non-NEN advanced malignancies [ 80 ], as well as patients with advanced NENs in other non-pancreatic locations (i.e., carcinoids) [ 6 , 29 , 76 , 77 , 78 , 79 ]. While the acquired resistance to therapy with targeted molecular therapies (i.e., mTOR inhibitors, Tyrosine kinase inhibitors) in patients with advanced panNENs/other NENs has received particular attention [ 6 , 21 , 29 , 75 , 77 , 78 , 81 ]; both primary and acquired resistance occur with the other forms of nonsurgical anti-tumor therapies in these patients to varying degrees ( Figure 1 ). As is apparent from this figure ( Figure 1 ), a significant degree of resistance is seen with all therapies, including somatostatin analogues, PRRT, chemotherapy and targeted therapy.…”