Homo sapiens
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PROVIDER: PRJNA301129 | ENA |
REPOSITORIES: ENA
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Project description:Abstract BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC. Gene expression profiles were generated for 95 breast tumors using Agilent Human 44K v5 microarrays following the manufacturer protocol. Stratagene Universal Human Reference RNA was used as the common control sample.
2016-08-21 | E-GEOD-74667 | biostudies-arrayexpress
Project description:Abstract BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.
2016-08-21 | GSE74667 | GEO
Project description:Combination therapy with Smo and PI3K inhibitors results in a synergistic effect in reducing tumor growth in PTEN-deficient Glioblastoma. To identify consequences of combination therapy with an Smo inhibitor and a PI3K inhibitor on a genome-wide scale, we performed Affymetrix microarrays with two different PTEN-deficient GBMs treated with single drugs or combination therapy. A small set of genes was significantly affected by combination therapy in hBT70 and/or hBT112, including several genes implicated in GBM prognosis, or identified as targets of Shh, PI3K or S6 pathways 29-33 . There are two different human GBM tumors (BT70 and BT112). Both are PTEN deficient. Samples were treated with DMSO (Control), LDE225 at 1 uM for 5 days, BKM 120 100 nM for 5 days, or LDE225 1 uM and BKM 120 100 nM for 5 days (Combo). Two biological replicates of each condition were analyzed.
2013-09-01 | E-GEOD-49416 | biostudies-arrayexpress
Project description:Combination therapy with Smo and PI3K inhibitors results in a synergistic effect in reducing tumor growth in PTEN-deficient Glioblastoma. To identify consequences of combination therapy with an Smo inhibitor and a PI3K inhibitor on a genome-wide scale, we performed Affymetrix microarrays with two different PTEN-deficient GBMs treated with single drugs or combination therapy. A small set of genes was significantly affected by combination therapy in hBT70 and/or hBT112, including several genes implicated in GBM prognosis, or identified as targets of Shh, PI3K or S6 pathways 29-33 .
2013-09-01 | GSE49416 | GEO
Project description:Sarcomas encompass heterogenous, difficult to treat cancers, lacking common therapeutic targets. Phosphatidylinositol-3 kinase (PI3K) signaling is activated in sarcomas to a greater degree than previously appreciated due to phosphatase and tensin homolog (PTEN) loss, and could represent such a target. Targeting PI3K signaling has largely focused on targeting mTORC1, considered the main effector of PI3K signaling, but this has not translated to success in the clinic, suggesting that there may be other effectors downstream of PI3K. One gap in our understanding of the PI3K signaling pathway has been the absence of a known oncogenic transcription factor. Herein we implicate TAZ and YAP as additional transcriptional effectors downstream of PI3K signaling regulated by a LATS1/2 dependent mechanism. Using in vitro and in vivo approaches, we show that TAZ and YAP are central oncoproteins in PI3K driven oncogenesis along with mTORC1, providing a rationale for combination therapy. Leveraging these findings, we describe a therapeutic approach that builds upon pre-existing therapeutic strategies utilizing mTORC1 inhibitors and combines them with new TEAD inhibitors that target YAP and TAZ. Combination therapy using everolimus and IK-930, an inhibitor targeting autopalmitoylation of the TEADs, synergistically diminished proliferation and anchorage dependent growth of PI3K activated sarcoma cell lines at low, physiologically achievable doses. In vivo, this combination therapy showed a synergistic effect, contrasting with the lack of effect of the individual single agent therapies, suggesting that an integrated view of PI3K and Hippo signaling can be leveraged therapeutically in PI3K activated sarcomas.
2024-10-01 | GSE274982 | GEO
Project description:Activation of the PI3K pathway in estrogen receptor α (ER)-positive (+) breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. PTEN is a negative regulator of the PI3K pathway typically lost in ER-negative (-) breast cancer. To clarify the effect of PTEN down-regulation on the response of ER+/HER2- breast cancer to endocrine therapy, we established reduced PTEN cell models using inducible knockdown. We found that only moderate PTEN reduction is sufficient to enhance PI3K signaling, generate a gene signature associated with luminal B subtype, and cause endocrine resistance. Combining endocrine therapy with mTOR, AKT, or MEK inhibitors improves antitumor activity, but the efficacy varies by type of endocrine therapy and the specific inhibitor. Fulvestrant plus an AKT inhibitor is the most potent combination when PTEN is reduced, inducing apoptosis and tumor regression. This combination deserves further study in patients with PI3K pathway activation.
2014-06-30 | GSE53300 | GEO
Project description:Introduction Basal-like (BLCs) and epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers which have the more aggressive clinical behavior. In contrast to HER2+ carcinomas, no targeted therapy is currently available for the treatment of patients with BLCs. In order to discover potential therapeutic targets, we searched for deregulated signaling pathways in human BLCs. Methods In this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in twelve BLCs, and compared it to a control series of eleven hormonal receptor negative- and grade III- matched HER2+ carcinomas. The two tumor populations were first characterized by immunohistochemistry and gene expression. The PI3K pathway was then investigated by gene copy-number analysis, gene expression profiling and at a proteomic level using reverse phase protein array technology and tissue microarray. The effects of PI3K inhibition pathway on proliferation and apoptosis was further analyzed in three human basal-like cell lines. Results The PI3K pathway was found to be activated in BLCs and up-regulated compared to HER2+ tumors as shown by a significantly increased activation of the downstream targets Akt and mTOR. BLCs expressed significantly lower levels of the tumor suppressor PTEN and PTEN levels correlated negatively in a significant manner with Akt activity within that population. PTEN protein expression correlated significantly with PTEN DNA copy number and more importantly, reduced PTEN DNA copy numbers were observed specifically in BLCs. Similarly to human samples, basal-like cell lines exhibited an activation of PI3K / Akt pathway and low/lack PTEN expression. Both PI3K and mTOR inhibitors led to basal-like cell growth arrest. However, apoptosis was observed specifically after PI3K inhibition.
2008-12-03 | GSE13787 | GEO
Project description:Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated by a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.
2024-11-06 | GSE269881 | GEO
Project description:Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated by a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.
2024-11-06 | GSE269880 | GEO
Project description:Oncogenic signals often activate abnormal proliferation, while simultaneously activate stress-adaptive mechanisms such as the integrated stress response (ISR) to ensure rapid growth under intrinsic and extrinsic stress conditions. In this study, we investigated the involvement of EGFR-PI3K pathway in the regulation of ISR in EGFR-mutant NSCLC cell lines under amino acid deprivation. We found that the third generation EGFR inhibitor osiemrtinib suppressed induction of activation transcription factor 4 (ATF4), the key ISR effector, in EGFR mutant cells, while the effect was to a less extent in cells harboring PIK3CA-co-alteration. PI3K inhibitors including P110a-specific inhibitor alpelicib markedly suppress ATF4 induction in PIK3CA-mutant cell lines. To further explore the role of EGFR-PI3K, transcriptome analysis was performed in EGFR- and PIK3CA-mutated NCI-H1975 cells treated with osimertinib, alpelisib, or combination of these in the absence or presence of histidyl-tRNA inhibitor L-histidinol (His), mimicking amino acid deprived conditions. Among His-induced genes, either osimertinib or alpelisib partially, but the combination dramatically suppressed a cluster of genes targeted by ATF4. Furthermore, combination of osimertinib and alpelisib increased apoptotic cells under amino acid deprived conditions. These results indicate that oncogenic EGFR-PI3K pathway contributes to cellular adaptation to stress conditions through ATF4. We used microarrays to identify genes whose expression is up- or down-regulated by inhibition of EGFR, PI3K, or both under amino acid deprivation.
2023-03-22 | GSE216508 | GEO