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The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.

ABSTRACT: Previously, we showed that inhibition of the protein kinase C ? (PKC?)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines, primary non-Hodgkin Lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) cells were simultaneously treated with the HDI, LBH589 and GS-1101. An interaction of the LBH589/GS-1101 combination was formally examined by using various concentrations of LBH589 and GS-1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI3K signalling dramatically increases HDI-mediated apoptosis in malignant haematopoietic cells, possibly through both AKT-dependent or AKT- independent mechanisms. Moreover, the increase in HDI-related apoptosis observed in PI3K inhibitor-treated cells appears to be related to the disruption of the extracellular signal-regulated kinase (ERK) signalling pathway. This study provides a strong rational for testing the combination of PI3K inhibitors and HDI in the clinic.

SUBMITTER: Bodo J

PROVIDER: S-EPMC3784300 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.

Bodo Juraj J Zhao Xiaoxian X Sharma Arishya A Hill Brian T BT Portell Craig A CA Lannutti Brian J BJ Almasan Alexandru A Hsi Eric D ED

British journal of haematology 20130725 1

Previously, we showed that inhibition of the protein kinase C β (PKCβ)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines, primary non-Hodgkin L ...[more]

PMID: 23889282

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Project description:BackgroundErlotinib is a commonly used epidermal growth factor receptor (EGFR)-targeted therapeutic choice for head and neck squamous cell carcinoma; however, its efficacy is largely compromised by cancer cell resistance. Understanding and targeting the erlotinib adaptive mechanisms of squamous cell carcinoma of the head and neck (HNSCC) cancer cells are still pressing challenges. This study aimed to elucidate the cooperative erlotinib-sensitizing mechanisms of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K) co-inhibition, which will be helpful in gaining a better understanding of the mechanism of EGFR-tyrosine kinase inhibitor (TKI) resistance in head and neck cancer cells.MethodsHigh-content screening (HCS) was performed to analyze the cell counts of different treatment groups and their drug-sensitizing effect phenotype. Western blotting and immunofluorescence staining assays were used to measure and locate the expression of proteins in the FaDu and TU212 cells. Annexin V/PI and DAPI staining were also used to determine the ratio of apoptotic cells and different cell cycle phases.ResultsThe expression of phosphor-EGFRTyr992 was significantly increased in erlotinib-treated FaDu cells compared with dimethyl sulfoxide (DMSO)-treated FaDu cells. Meanwhile, erlotinib + vorinostat + copanlisib jointly attenuated the expression of phosphor-EGFRTyr1068 and phosphor-EGFRTyr992, but stimulated the expression of E-cadherin. Moreover, we found that the tri-drug group also impaired the expression of phosphor-STAT3Ser727 and its relevant activators, including phosphor-SrcTyr416.ConclusionsThese findings indicate that HDACs and PI3K co-inhibition sensitizes erlotinib via inactivation of the phosphor-EGFRTyr1068-induced RTK-STAT3 axis. However, PI3K inhibition was sufficient to sensitize TU212 cells to erlotinib, providing new perspectives for the further clinical study of erlotinib + vorinostat + copanlisib as a potential combination therapeutic solution for EGFR responsive reactivation-induced resistance to erlotinib.

Project description:Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase ? offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3K? and Bruton's tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton's tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-I?B?. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton's tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the combination of idelalisib and ONO/GS-4059 (NCT02457598).

Dataset Information

The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.

Publications

The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.

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