Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors

Abstract

Purpose Mutations in the PI3-kinase (PI3K) pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacological intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. Experimental Design In the present study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α selective (GDC-0326) inhibitors and isoform specific PI3K kinase-dead mutant mice. Results Human and mouse PanNETs showed enhanced pAKT, pPRAS40 and pS6 positivity compared to normal tissue. While treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node (LN) metastasis compared to vehicle treated mice. We also demonstrated that tumor and stromal cells are implicated in the anti-tumor activity of GDC-0326 in RIP1-Tag2 tumors. Conclusion Our data provide a rationale for p110α selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis.

Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms

“…Several works in vitro have shown that the accumulation of p-AKT could lead to secondary resistance to mTOR inhibitors, but there are no data with tyrosine kinase inhibitors such as sunitinib [21]. Recent data had demonstrated positivity for p-AKT in NET but had failed to demonstrate any significant association between p-AKT and prognosis, tumour grade or other clinicopathological variables [22-24]. Nevertheless, Falletta et al [25] showed that p-AKT could be a possible predictive marker of response to everolimus in primary cultures of PanNET and could help identify patients who could benefit from this therapy.…”

Molecular Pathogenesis of Pancreatic Cancer

“…2A). The activation of mTORCI is a key feature of many PDACs that results in increased protein translation, stem cell renewal, proliferation, and inhibition of autophagy via ULK1 kinase activation 94,95 .…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Network wiring from RTK to PIK3CA/mTOR and MEK/ERK signaling is reasonably well understood; however, the influence of genetic alterations found in neuroendocrine tumors, including TSC2, AKT and PTEN alterations onto network behavior during therapeutic interference is unknown and is currently explored in NET (http://www.sys-med.de/ de/demonstratoren/maptor-net). Recently published experimental work provided novel ideas on how network behavior in the context of specific genetic alterations can have an influence on therapy (François et al 2015, Schwartz et al 2015, Soler et al 2016, Xu et al 2016. Selective inhibition of PIK3CAβ in PTEN-deficient cancers results only in a transient suppression of AKT/mTOR activity due to feedback-dependent activation of RTKs and subsequent activation of PIK3CAα (Schwartz et al 2015).…”

“…Only dual inhibition of both isoforms resulted in sustained pathway suppression and inhibition of tumor cell survival. Also, Soler and coworkers describe both a growth-suppressive and angiogenesis-suppressive effect of the selective p110 PIK3CA inhibitor in the RipTag2 mouse model for pNET upon combination with the pan-PI3K inhibitor (GDC-0941) (Soler et al 2016). Although only selected papers are mentioned here, it becomes clear that for successful targeted therapy in NET, a much deeper understanding of pathway wiring, feedback control and role of the deregulated genes is urgently required.…”