PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors

Abstract

Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway have a key role in the pathogenesis of numerous cancers by altering cell growth, metabolism, proliferation and apoptosis. Interest in targeting the PI3K signaling cascade continues, as new agents are being clinically evaluated. PIK3CA mutations result in a constitutively active PI3K and are present in a subset of pancreatic cancers. Here we examine mutant PIK3CA-mediated pancreatic tumorigenesis and the response of PIK3CA mutant pancreatic cancers to dual PI3K/mammalian target of rapamycin (mTOR) inhibition. Two murine models were generated expressing a constitutively active PI3K within the pancreas. An increase in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasms (PanINs) was identified. In one model these lesions were detected as early as 10 days of age. Invasive pancreatic ductal adenocarcinoma developed in these mice as early as 20 days of age. These cancers were highly sensitive to treatment with dual PI3K/mTOR inhibition. In the second model, PanINs and invasive cancer develop with a greater latency owing to a lesser degree of PI3K pathway activation in this murine model. In addition to PI3K pathway activation, increased ERK1/2 signaling is common in human pancreatic cancers. Phosphorylation of ERK1/2 was also investigated in these models. Phosphorylation of ERK1/2 is demonstrated in the pre-neoplastic lesions and invasive cancers. This activation of ERK1/2 is diminished with dual PI3K/mTOR inhibition. In summary, PIK3CA mutations can initiate pancreatic tumorigenesis and these cancers are particularly sensitive to dual PI3K/mTOR inhibition. Future studies of PI3K pathway inhibitors for patients with PIK3CA mutant pancreatic cancers are warranted.

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

“…In line with this finding, ADM, PanIN and the formation of invasive PDAC can also be observed after transgenic expression of a constitutively-active form of p110α 82 . PI3K-mediated transdifferentiation of acinar cells is mediated through ERK1/2 signalling 82 , and small molecule inhibitors targeting the activation of ERK1/2 indicate that these MAP kinases are involved in Kras G12D -driven dedifferentiation of acinar cells, ADM and PanIN formation 11,83 . To drive these processes, PI3K also initiates actin reorganization processes that are orchestrated by Rho GTPases 80,81,84 .…”

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…In addition, recent large-scale, pan-cancer proteogenomic studies have identified molecular alterations in several Src effector networks including PI3K/Akt/ mTOR and FAK [80,[126][127][128]. The PI3KCA gene mutations present in 3-5% of pancreatic cancer patients can act as activating mutations initiating pancreatic tumour formation [129]. In PDAC specifically,~17% of tumours carried alterations, the majority of which involved gene amplification, and this finding is consistent across multiple cohorts [114,115] (Fig.…”

HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer

“…Pancreatic cancer is one of the most aggressive solid malignancies with an extremely poor prognosis of an overall 5-year survival rate of <5% [1]. Without a specific diagnostic marker and symptom in early stage, pancreatic cancer is often diagnosed at an advanced/late stage and only palliative measures can be offered [2].…”

“…Aberrations of the PI3K signaling induces the pathogenesis of numerous cancers by altering cell growth and apoptosis [1]. Vichalkovski et al have reported that activation of AKT upregulated the expression of Twist, subsequently decreasing chemotherapy-induced DNA damage, and inhibiting apoptosis [21].…”