PKI-587 and Sorafenib Targeting PI3K/AKT/mTOR and Ras/Raf/MAPK Pathways Synergistically Inhibit HCC Cell Proliferation

Gedaly, Roberto; Angulo, Paul; Hundley, Jonathan C.; Daily, Michael F.; Chen, Changguo; Evers, B. Mark

doi:10.1016/j.jss.2011.10.045

Cited by 86 publications

(67 citation statements)

References 26 publications

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“…One mechanism of sorafenib resistance in cultured HCC cells may be associated with a switch from the MAPK pathway to the parallel PI3K/Akt pathway when vascular endothelial growth factor receptor (VEGFR), plateletderived growth factor receptor (PDGFR), Ret, c-kit and the downstream MAPK pathway are inhibited by sorafenib inhibition of tyrosine kinases. Activation of Akt and upregulation of phosphorylation of its downstream targets, including S6K and 4EBP1, have been shown in sorafenib treated HCC cells [7]. In HCC cells in which resistance is the result of long-term exposure to sorafenib, increased expression of phosphorylated Akt and the p85 regulatory subunit of PI3K was observed.…”

Section: Pi3k/akt Pathway Is Involved In the Sorafenib Resistancementioning

confidence: 95%

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to underlying co-morbid cirrhosis and chemo-resistance. Vaccination and improved treatment for hepatitis are the most effective means to reduce the burden of liver cancer worldwide. Expression of biomarkers such as AFP (alpha-fetoprotein), DDK1 (Dickkopf WNT Signaling Pathway Inhibitor 1) and microRNAs in blood are being tested for early screening of liver cancer. Since 2008, sorafenib has been used as the standard molecular targeting agent for HCC. However, overall outcomes for sorafenib alone or in combination with other tyrosine kinase inhibitors are unsatisfactory. Whether simultaneously or sequentially, addiction switches and compensatory pathway activation in HCC, induced by sorafenib treatment, may induce acquired resistance. Forkhead box M1 (FOXM1) and metadherin (MTDH) have been shown to be master regulators of different aspects of tumorigenesis, including angiogenesis, invasion, metastasis and drug resistance. Elevated expression of both FOXM1 and MTDH is known to be a consequence of both activating mutations in oncogenes such as PI3K, Ras, myc and loss of function mutations in tumor suppressor genes such as p53 and PTEN in various types of cancers including HCC. The role of FOXM1 and MTDH as potential prognostic markers as well as therapeutic targets in HCC will be discussed. In addition, microRNAs (miRNAs), endogenous small noncoding RNAs involved in the regulation of gene expression, are involved in HCC and interact with both FOXM1 and MTDH in several ways. Thus, altered expression of miRNAs in HCCs will also be discussed as potential tools for diagnosis, prognosis and therapy in HCC. OPEN ACCESS

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Section: Pi3k/akt Pathway Is Involved In the Sorafenib Resistancementioning

confidence: 95%

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

et al. 2014

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“…Ras/MAPK and AKT/mTOR pathways are frequently deregulated in human hepatocarcinogenesis [141]. The combination of PKI-587, targeting PI3K/AKT/mTOR pathway and sorafenib, mainly targeting Ras/ Raf/MAPK signaling pathways, has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both the signaling pathways simultaneously [142]. Additionally, results of an ongoing, randomized, open-label, phase II study are awaited, which would compare the efficacy of everolimus, targeting PI3K/AKT/ mTOR pathway, combined with sorafenib to sorafenib alone (ClinicalTrials.gov identifier NCT01005199).…”

Section: Combination Of Targeted Agentsmentioning

confidence: 99%

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

et al. 2015

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“…Because of several cross-activating connections between the PI3K/AKT/mTOR and other mitogen pathways, the dual inhibition of PI3K/mTOR can lead to increased activity in ERK signaling [26,40] . For all four cell lines, our data ascertained PKI-587-induced activation of ERK signaling and therefore activation of MAPK signaling as an escape mechanism (Western blot; table 1 ).…”

Section: Induction Of Erk Signaling and Minor Relevance Of Feedback Amentioning

confidence: 99%

Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease

Freitag

Christen²,

Lewens³

et al. 2016

Neuroendocrinology

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Background: The characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, the current therapy options are not satisfactory. PKI-587 is a highly potent, novel dual inhibitor of PI3K and mTORC1/C2. Aim: We assessed the effects of PKI-587 in different GEP-NEN tumor models, including the poorly differentiated cell line LCC-18, and compared them with those of the established mTORC1 inhibitor everolimus. Methods: We treated BON, QGP-1, KRJ-I, and LCC-18 cell lines with increasing concentrations of the inhibitor PKI-587, and compared the results with those of everolimus and DMSO. We assessed the impact of the treatments on viability (WST-1 assay), on apoptotic processes (caspase 3/7 assay, JC-1), and on cell cycle regulation (flow cytometry). We determined alterations in signaling mediators by phosphor-specific Western blot analysis and conducted multiplexed gene expression analysis (nCounter® technology). Results: In all cell lines, PKI-587 dose-dependently inhibited proliferation, whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest and induction of apoptosis and successfully suppressed activity of the direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT, and PI3K pathway genes after treatment. Treatment-dependent and cell line-characteristic effects on AKT/Rb/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this paper. Conclusion: PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials.

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PKI-587 and Sorafenib Targeting PI3K/AKT/mTOR and Ras/Raf/MAPK Pathways Synergistically Inhibit HCC Cell Proliferation

Cited by 86 publications

References 26 publications

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease

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