Abstract
Simple SummaryPancreatic 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.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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy emerging as one of the most frequent causes of cancer-related deaths globally [1,2,3]
The PDAC tumor microenvironment (TME) is characterized by a dense stromal network comprised of non-neoplastic cells, extracellular matrix components, and the presence of immunosuppressive cells constituting mainly myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells [51,52,53]
Along similar lines, using a highly aggressive PKT GEMM mouse of PDAC that phenocopies human disease in terms of dense stroma and presence of immunosuppressive milieu [57], previously we have demonstrated that combined inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) using Urolithin A effectively reprograms the fibroinflammatory tumor stroma to promote an anti-tumor immune microenvironment by decreasing immunosuppressive TAMs and augmenting T-cell recruitment within the TME of PDAC (Figure 2) [15]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy emerging as one of the most frequent causes of cancer-related deaths globally [1,2,3]. Cancers 2021, 13, x Cancers 2021, 13, 4434 recent advances in surgical care and chemotherapy regimens, only a modest improvement in survival has been observed with this disease. This suggests a clear need to improve our iunnsduerrvsitvaanldhinags boefetnheobisoelrovgeydowf PitDh AthCistodifsaecailsieta. .SScchheemmaatitcicrerepprerseesnentatatitoionnofofPIP3IK3K//AAKKTT//mmTTOORR ssiiggnnaalliinngg ppaatthhwwaayyaannddititssimimpplilcicaatitoionnoonn cceelllululalarrpprroocceesssseess..TThheeiimmaaggee wwaass ccrreeaatteedd wwiitthh BBiiooRReennddeerr..ccoomm((AAggrreeeemmeennttnnuummbbeerr ZZSS2222VVAAMMSSIIDD,, aacccceesssseeddoonn2233AAuugguusstt22002211).). An increase in the activation of the PI3K signaling is associated with poor overall survival in PDAC patients [16,17]. PI3K-dependent activation of the mTORC2 complex is mediated via increased AKT phosphorylation [30] These mTORs enhance the translational ability of several mRNAs in combination with other accessory protein complexes [31,32]. Investigators have previously shown that in a Pdx1CRE mouse model, conditional deletion of PTEN with mutant K-Ras within the pancreas accelerates the development of premalignant neoplasm via promoting ADM formation [36,37]
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