Phosphoinositide 3-Kinase Signaling Pathway in Pancreatic Ductal Adenocarcinoma Progression, Pathogenesis, and Therapeutics.

Divya Murthy,Pankaj K Singh,Kuldeep S Attri

doi:10.3389/fphys.2018.00335

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by its sudden manifestation, rapid progression, poor prognosis, and limited therapeutic options. Genetic alterations in key signaling pathways found in early pancreatic lesions are pivotal for the development and progression of pancreatic intraepithelial neoplastic lesions into invasive carcinomas. More than 90% of PDAC tumors harbor driver mutations in K-Ras that activate various downstream effector-signaling pathways, including the phosphoinositide-3-kinase (PI3K) pathway. The PI3K pathway also responds to stimuli from various growth factor receptors present on the cancer cell surface that, in turn, modulate downstream signaling cascades. Thus, the inositide signaling acts as a central node in the complex cellular signaling networks to impact cancer cell growth, motility, metabolism, and survival. Also, recent publications highlight the importance of PI3K signaling in stromal cells, whereby PI3K signaling modifies the tumor microenvironment to dictate disease outcome. The high incidence of mutations in the PI3K signaling cascade, accompanied by activation of parallel signaling pathways, makes PI3K a promising candidate for drug therapy. In this review, we describe the role of PI3K signaling in pancreatic cancer development and progression. We also discuss the crosstalk between PI3K and other major cellular signaling cascades, and potential therapeutic opportunities for targeting pancreatic ductal adenocarcinoma.

Highlights

Pancreatic cancer is the third-leading cause of cancer-related morbidity in the United States, owing largely to the short-term survival rates observed for pancreatic cancer patients despite a low incidence rate (Mazure et al, 1997; Siegel et al, 2016; Attri et al, 2017)
Previous in vitro screens reveal that Pancreatic adenocarcinoma (PDAC) cell lines are relatively resistant to single-agent therapies and targeting multiple nodes of the PI3K-Akt-mechanistic target of rapamycin (mTOR) signaling cascade using combination drug therapies might reinforce the response to individual drug therapies
K-rat sarcoma virus (Ras) and PI3K are key regulated nodes in the complex, inter-connected signaling networks altered during pancreatic cancer (Jones et al, 2008)

Summary

Introduction

Pancreatic cancer is the third-leading cause of cancer-related morbidity in the United States, owing largely to the short-term survival rates observed for pancreatic cancer patients despite a low incidence rate (Mazure et al, 1997; Siegel et al, 2016; Attri et al, 2017). The genetically engineered mouse models expressing these oncogenic mutations result in constitutive activation of K-Ras, that regulates downstream signaling pathways involved in proliferation, migration, and metastasis of cancer cells (di Magliano and Logsdon, 2013). In addition to K-Ras, the PI3K can be activated by a variety of oncogenic mutations and growth factor receptors present on the surface of cancer cells.

Results

Conclusion