Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

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.

An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer

“…The altered KRAS modulates many signaling pathways including phosphatidylinositol 3-kinase (PI3K) signaling. Disruptions in P13K signaling and its subsequent downstream signaling components significantly regulate various oncogenes that are involved in various cancers, including PDAC ( 52 ). Apart from KRAS dependent regulation, P13K signaling cascade activation is associated with growth factor stimuli and cytokines.…”

“…Cytokines enter the cancer cells through high affinity cell surface receptors, known as receptor tyrosine kinases (RTKs). After initiation, P13K downstream signaling mediates various oncogenic functions like cancer cell metabolism, growth, and movement by further activating other signaling pathways ( 52 ).…”

“…In some cancers (breast and ovarian non-small cell lung cancer (NSLC), inhibition of P13K signaling nodes has revealed promising outcomes. However, in PDAC, inhibition of the P13K cascade by using monotherapies of these same drugs (small molecule inhibitors), has not resulted in a favorable therapeutic effect ( 52 ). In recent times, the focus has been shifted to a combinatorial regimen rather than relying on monotherapy.…”

“…In recent times, the focus has been shifted to a combinatorial regimen rather than relying on monotherapy. To efficiently thwart the tumor development in PDAC, P13K inhibition along with its downstream pathway is suggested by using P13K specific inhibitors and molecule attenuators of downstream signaling ( 52 ).…”

5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT, and ERK Activity

“…A striking feature of pancreatic cancer is that mutationally activated K-ras is present in ∼90% of PDAC cases. As a key downstream target of the Ras family, AKT activation is a frequent event and correlates with the outcome in approximately 60% of pancreatic cancers [54]. Overexpression and activation of AKT has been associated with worse prognostic variables and outcome, as well as the apoptotic effect of chemotherapy [55,56].…”