Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

SIMPLE SUMMARY: Pancreatic cancer has a dismal 5-year survival rate of 10%, making it one of the deadliest forms of malignancy. The poor prognosis associated with this disease is because it is resistant to almost every type of chemotherapy. Another major hallmark of pancreatic cancer is the presence of several activated oncogenic signaling pathways, including PI3K/Akt/mTOR, which promotes disease aggressiveness and therapeutic resistance. Previously, we have shown that targeted inhibition of PI3K/Akt/mTOR together led to a significant reduction of tumor burden and improvement of overall survival in an aggressive mouse model of pancreatic cancer. This review article discusses the significance of targeting PI3K and its direct downstream effector components in pancreatic cancer. Additionally, we will also update on the recent studies highlighting the tumor cell-extrinsic impact of PI3K inhibition in the modulation of the immune microenvironment within the context of this malignancy. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest solid tumors that remain treatment-refractory and show a dismal prognosis. More than 90% of PDAC tumors harbor mutations in the K-Ras that exert a strong pro-tumorigenic effect by activating several downstream effector pathways, including phosphatidylinositol-3-kinase (PI3K)-Akt. The role of frequently activated PI3K/Akt pathway in promoting PDAC aggressiveness is well established. Therapeutic approaches targeting PI3K and downstream signaling components in different cellular compartments, including tumor, stromal and immune cells, have directly impacted the tumor burden in this cancer type. Our previous work has demonstrated that targeting the PI3K/Akt/mTOR pathway reduced tumor growth and improved survival in the genetic mouse model of PDAC. Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor–stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.