70 results found
Coombes RC, Badman PD, Lozano-Kuehne JP, et al., 2023, Author Correction: Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer., Nature Communications, Vol: 14, Pages: 1-1, ISSN: 2041-1723
Williams R, Schaf J, Shinhmar S, et al., 2022, Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth
<jats:title>Abstract</jats:title> <jats:p>Glioblastomas are a highly aggressive cancer type which respond poorly to current pharmaceutical treatments, thus novel therapeutic approaches need to be investigated. One such approach involves the use of the bioactive natural product tanshinone IIA (T2A) derived from the Chinese herb Danshen, where mechanistic insight for this anti-cancer agent is needed to validate its use. Here, we employ a tractable model system, <jats:italic>Dictyostelium discoideum</jats:italic>, to provide this insight. T2A potently inhibits cellular proliferation of <jats:italic>Dictyostelium</jats:italic>, suggesting molecular targets in this model. We show that T2A rapidly reduces phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB) activity, but surprisingly, the downstream complex mechanistic target of rapamycin complex 1 (mTORC1) is only inhibited following chronic treatment. Investigating regulators of mTORC1, including PKB, tuberous sclerosis complex (TSC), and AMP-activated protein kinase (AMPK), suggests these enzymes were not responsible for this effect, implicating an additional molecular mechanism of T2A. We identify this mechanism as the increased expression of <jats:italic>sestrin</jats:italic>, a negative regulator of mTORC1. We further show that combinatory treatment using a PI3K inhibitor and T2A gives rise to a synergistic inhibition of cell proliferation. We then translate our findings to human and mouse-derived glioblastoma cell lines, where both a PI3K inhibitor (Paxalisib) and T2A reduces glioblastoma proliferation in monolayer cultures and in spheroid expansion, with combinatory treatment significantly enhancing this effect. Thus, we propose a new approach for cancer treatment, including glioblastomas, through combinatory treatment with PI3K inhibitors and T2A.</jats:p>
Khalil MI, Ismail HM, Panasyuk G, et al., 2022, Asymmetric dimethylation of Ribosomal S6 Kinase 2 regulates its cellular localisation and pro-survival function
<jats:title>Abstract</jats:title><jats:p>Ribosomal S6 Kinases (S6Ks) are critical regulators of cell growth, homeostasis, and survival, with dysregulation of these kinases being associated with various malignancies. While S6K1 has been extensively studied, S6K2 has been neglected despite its reported involvement in cancer progression. Protein arginine methylation is a widespread post-translational modification regulating a plethora of biological responses in mammalian cells. Here we report that p54-S6K2 is asymmetrically dimethylated at Arg-475 and Arg-477, two conserved residues within the AT-hook motif of the S6K2 family and some AT-hook-containing proteins. We demonstrate that PRMT1, PRMT3, and PRMT6 bind to and methylate S6K2<jats:italic>in vitro</jats:italic>and<jats:italic>in vivo</jats:italic>. This methylation localises S6K2 to the nucleus where it rescues cells from starvation-induced cell death. Taken together, our findings highlight a novel mechanism regulating the biological function of p54-S6K2 that may be relevant to cancer where Arg-methylation is often found elevated.</jats:p>
Chen S, Seckl MJ, Lorentzen MPG, et al., 2022, Differential expression of RSK4 transcript isoforms in cancer and its clinical relevance
<jats:title>Abstract</jats:title><jats:p>RSK4 belongs to the p90 Ribosomal S6 Kinase family which lies downstream of the MAPK pathway. While we previously revealed this kinase to be a therapeutic target in lung and bladder cancers, there is conflicting evidence for its wider role in other cancer types. Indeed, RSK4 was instead suggested to be a tumour suppressor in colorectal and gastric cancers, and reports of its role in breast malignancies are contradictory. One possible explanation for these discrepancies may be the expression of different RSK4 isoforms across cancers. Four RNAs are produced from the RSK4 gene with two being protein-coding. Here, we analysed the expression of the two RSK4 protein-coding mRNAs across 30 normal and 33 cancer tissue types from the combined GTEx/TCGA dataset and correlated it with associated clinical features. This analysis revealed the mRNA expression of RSK4 isoform 1 and 2 to be independent prognostic factors for patient survival, pathological stage, cancer metastasis, recurrence, and immune infiltration in brain, stomach, cervical, and kidney cancers. However, we found that the upregulation of either RSK4 isoform can equally be associated with good or bad prognosis depending on the cancer type considered, and changes in the expression ratio of isoforms fail to predict clinical outcome. Taken together, we show that differential isoform expression alone cannot explain the contradictory roles of RSK4 in cancers and that further research is needed to highlight the underlying mechanisms for the context-dependent function of this kinase.</jats:p>
Coombes R, Badman P, Lozano-Kuehne JP, et al., 2022, Results of the Phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer, Nature Communications, Vol: 13, ISSN: 2041-1723
We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients’ samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.
Georgiou M, Ntavelou P, Stokes W, et al., 2022, ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma (vol 4, pg 2540, 2022), ONCOGENE, Vol: 41, Pages: 3510-3510, ISSN: 0950-9232
Georgiou M, Ntavelou P, Stokes W, et al., 2022, ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma, ONCOGENE, Vol: 41, Pages: 2540-2554, ISSN: 0950-9232
- Author Web Link
- Citations: 2
Pardo O, Chrysostomou S, Roy R, et al., 2021, Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer, Science Translational Medicine, Vol: 13, ISSN: 1946-6234
Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.
Chrysostomou S, Roy R, Prischi F, et al., 2019, Abstract 1775: Targeting RSK4 prevents both chemoresistance and metastasis in lung cancer, AACR Annual Meeting on Bioinformatics, Convergence Science, and Systems Biology, Publisher: American Association for Cancer Research, Pages: 1-2, ISSN: 0008-5472
Lung cancer is the commonest cause of cancer death worldwide with a five-year survival rate of less than five percent for metastatic tumors. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases of which adenocarcinoma prevails. Patients almost invariably develop metastatic drug-resistant disease and this is responsible for our failure to provide curative therapy. Hence, a better understanding of the mechanisms underlying these biological processes is urgently required to improve clinical outcome.The 90-kDa ribosomal S6 kinases (RSKs) are downstream effectors of the RAS/MAPK cascade. RSKs are highly conserved serine/threonine protein kinases implicated in diverse cellular processes, including cell survival, proliferation, migration and invasion. Four isoforms exist in humans (RSK1-4) and are uniquely characterized by the presence of two non-identical N- and C-terminal kinase domains. RSK isoforms are 73-80% identical at protein level and this has been thought to suggest overlapping functions.However, through functional genomic kinome screens, we show that RSK4, contrary to RSK1, promotes both drug resistance and metastasis in lung cancer. This kinase is overexpressed in the majority (57%) of NSCLC biopsies and this correlates with poor overall survival in lung adenocarcinoma patients. Genetic silencing of RSK4 sensitizes lung cancer cells to chemotherapy and prevents their migration and invasiveness in vitro and in vivo. RSK4 downregulation decreases the anti-apoptotic proteins Bcl2 and cIAP1/2 which correlates with increased apoptotic signalling, whilst it also induces mesenchymal-epithelial transition (MET) through inhibition of NFκB activity. A small-molecule inhibitor screen identified several floxacins, including trovafloxacin, as potent allosteric inhibitors of RSK4 activation. Trovafloxacin reproduced all biological and molecular effects of RSK4 silencing in vitro and in vivo, and is predicted to bind a novel allosteric site revealed
Prischi F, Chrysostomou S, Roy R, et al., 2019, Targeting RSK4 prevents both chemoresistance and metastasis in lung and bladder cancer, FEBS Open Bio, Publisher: WILEY, Pages: 330-330, ISSN: 2211-5463
O'Flaherty L, Shnyder SD, Cooper PA, et al., 2019, Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer, PLoS ONE, Vol: 14, ISSN: 1932-6203
Glycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small celllung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomeson the metaphase plate during mitosis through regulation of microtubule stability. This makesthe enzyme an attractive target for cancer therapy. We examined the effects of a selectivecell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel,using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumorxenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC celllines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered asmonotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograftmodel. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically toinhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignmentduring metaphase. Our findings provide novel support for the use of the GSK3 inhibitor,CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer.
Pardo O, 2018, INHIBITION OF THE ATR PATHWAY AND CDK4/6 SIGNALLING AS NOVEL THERAPEUTIC STRATEGIES FOR METHOTREXATE-RESISTANT CHORIOCARCINOMA, Publisher: BMJ PUBLISHING GROUP, Pages: 200-200, ISSN: 1048-891X
Li H, Stokes WB, Chater E, et al., 2018, Resistance to tyrosine kinase-targeted therapy in lung cancer: Autophagy and metabolic changes, Meta Gene
© 2018 Lung cancer is the commonest cancer killer worldwide. Tyrosine-kinase inhibitors (TKI) are novel agents in the treatment of this cancer. However, their efficacy is impaired by the rapid development of drug-resistance through a variety of mechanisms. Here, we will discuss resistance to the first-generation EGFR inhibitors (e.g. Erlotinib) and SRC inhibitors (e.g. Dasatinib). The principal mechanism of resistance to first-generation EGFR inhibitors is the appearance of the T790M receptor mutation. While the reason for resistance was proposed to be changes in affinity of the receptor for ATP, our metabolomics analysis additionally revealed that resistance is associated with decreased cellular levels of glutathione (GSH), a direct consequence of the T790M mutation. This occurred because of decreased SQSTM1/NRF2-mediated transcription of GSH synthesising enzymes in cell lines and clinical samples with T790M-EGFR. We demonstrate that increasing GSH levels in resistant cells re-sensitises these to first-generation EGFR inhibitors in vitro and in vivo. As compounds exist in the clinic to achieve this, our finding may have profound therapeutic and economic consequences. Src family kinases (SFK) are commonly overexpressed or hyperactivated in lung cancer cell lines and clinical samples. However, despite their on-target efficacy, SRC inhibitors have failed to prevent tumour growth and improve patients’ survival in multiple clinical trial. Here we show that this failure is associated with the induction of autophagy in treated cells that prevents these compounds from triggering apoptosis cell death. Targeting autophagy, either genetically or using our novel small-molecule inhibitor, C1A, sensitises lung cancer cell lines to Dasatinib both in vitro and in vivo by unlocking the apoptotic response. These findings propose new combinational therapeutic strategies that could resurrect the use of SRC inhibitors in the treatment of lung cancer.
Pardo OE, Rupniewska E, Roy R, et al., 2018, Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors, Oncotarget, Vol: 9, Pages: 27346-27362, ISSN: 1949-2553
Lung cancer is the main cancer killer in both men and women, mostly due to the rapid development of drug resistant metastatic disease. Here, we evaluate the potential involvement of SRC family kinases (SFK) in lung cancer biology and assess the possible benefits of their inhibition as a therapeutic approach. We demonstrated that various SRC family members, including LYN and LCK, normally expressed solely in hematopoietic cells and neural tissues, are overexpressed and activated in a panel of SCLC and NSCLC cell lines. This was clinically relevant as LYN and FYN are also overexpressed in lung cancer clinical specimens. Moreover, LYN overexpression correlated with decreased patient survival on univariate and multivariate analysis. Dasatinib (BMS-354825), a SRC/ABL inhibitor, effectively blocked SFK activation at nanomolar concentrations which correlated with a significant decrease in cell numbers of multiple lung cancer cell lines. This effect was matched by a decrease in DNA synthesis, but only moderate induction of apoptosis. Indeed, dasatinib as well as PP2, another SFK inhibitor, strongly induced autophagy that likely prevented apoptosis. However, inhibition of this autophagic response induced robust apoptosis and sensitised lung cancer cells to dasatinib in vitro and in vivo. Our results provide an explanation for why dasatinib failed in NSCLC clinical trials. Furthermore, our data suggest that combining SFK inhibitors with autophagy inhibitors could provide a novel therapeutic approach in this disease.
Roy R, Pardo O, Seckl M, et al., 2017, Emerging roles of hnRNPA1 inmodulating malignanttransformation, Wiley Interdisciplinary Reviews: RNA, Vol: 8, ISSN: 1757-7004
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes such as processing of heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, RNA splicing, transactivation of gene expression, and modulation of protein translation. hnRNPA1 is the most abundant and ubiquitously expressed member of this protein family and has been shown to be involved in multiple molecular events driving malignant transformation. In addition to selective mRNA splicing events promoting expression of specific protein variants, hnRNPA1 regulates the gene expression and translation of several key players associated with tumorigenesis and cancer progression. Here, we will summarize our current knowledge of the involvement of hnRNPA1 in cancer, including its roles in regulating cell proliferation, invasiveness, metabolism, adaptation to stress and immortalization.
Poursaitidis I, Wang X, Crighton T, et al., 2017, Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine, CELL REPORTS, Vol: 18, Pages: 2547-2556, ISSN: 2211-1247
Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.
Li H, Stokes W, Chater E, et al., 2016, Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer, Cell Discovery, Vol: 2, ISSN: 2056-5968
Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.
Pardo OE, Munro CE, Castellano L, et al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO Reports, Vol: 17, Pages: 570-584, ISSN: 1469-221X
Here we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seqanalyses of both estrogen receptor-positive and negative breast cancer cells overexpressingmiR-515-5p reveals down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2Band MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3’UTRinteraction and that MARK4 knockdown mimics the effect of miR-515-5p on breast andlung cancer cell migration. MARK4 over-expression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation.Furthermore, miR-515-5p expression is reduced in metastases compared to primarytumours derived from both in vivo xenografts and samples from patients with breastcancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination ina mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expressioncorrelate with increased breast and lung cancer patients’ survival, respectively. Takentogether, these data demonstrate the importance of miR-515-5p/MARK4 regulation incell migration and metastasis across two common cancers.
Pardo OE, Arcaro A, Salerno G, et al., 2015, Fibroblast growth factor-2 induces translational regulation of Bcl-X-L and Bcl-2 via a MEK-dependent pathway. CORRELATION WITH RESISTANCE TO ETOPOSIDE-INDUCED APOPTOSIS (vol 277, pg 12040, 2002), JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 290, Pages: 15390-15390
- Author Web Link
- Citations: 1
Pardo OE, 2015, Meningioma dissemination and growth: a role for microRNAs, ONCOGENE, Vol: 34, Pages: 1743-1744, ISSN: 0950-9232
Schlegel CR, Georgiou ML, Misterek MB, et al., 2015, DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function, CELL DEATH & DISEASE, Vol: 6, ISSN: 2041-4889
- Author Web Link
- Open Access Link
- Citations: 13
Pardo OE, Arcaro A, Salerno G, et al., 2014, Novel cross talk between MEK and S6K2 in FGF-2 induced proliferation of SCLC cells (vol 20, pg 7658, 2014), ONCOGENE, Vol: 33, Pages: 5740-5740, ISSN: 0950-9232
Vincent EE, Elder DJE, O'Flaherty L, et al., 2014, Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation, PLOS ONE, Vol: 9, ISSN: 1932-6203
- Author Web Link
- Open Access Link
- Citations: 21
Roy R, Durie D, Li H, et al., 2014, hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling, Nucleic Acids Research, Vol: 42, Pages: 12483-12497, ISSN: 0305-1048
The increased cap-independent translation of anti-apoptotic proteins is involved in the development of drug resistance in lung cancer but signalling events regulating this are poorly understood. Fibroblast growth factor 2 (FGF-2) signalling-induced S6 kinase 2 (S6K2) activation is necessary, but the downstream mediator(s) coupling this kinase to the translational response is unknown. Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. In the cytoplasm, phosphoS4/6-hnRNPA1 dissociates from these mRNAs de-repressing their IRES-mediated translation. This correlates with the phosphorylation-dependent association of hnRNPA1 with 14-3-3 leading to hnRNPA1 sumoylation on K183 and its re-import into the nucleus. A non-phosphorylatible, S4/6A mutant prevented these processes, hindering the pro-survival activity of FGF-2/S6K2 signalling. Interestingly, immunohistochemical staining of lung and breast cancer tissue samples demonstrated that increased S6K2 expression correlates with decreased cytoplasmic hnRNPA1 and increased BCL-XL expression. In short, phosphorylation on novel N-term sites of hnRNPA1 promotes translation of anti-apoptotic proteins and is indispensable for the pro-survival effects of FGF-2.
Hoeland K, Boller D, Hagel C, et al., 2014, Targeting Class I-A PI3K Isoforms Selectively Impairs Cell Growth, Survival, and Migration in Glioblastoma, PLOS One, Vol: 9, ISSN: 1932-6203
The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110β expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110β also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6.
Kaliszczak M, Pardo OE, Seckl MJ, et al., 2013, HDAC6 inhibitor C1A abrogates the recruitment of the autophagic machinery and synergizes with proteasome, src kinase, and PI3K-mTOR inhibition., MOLECULAR CANCER THERAPEUTICS, Vol: 12, ISSN: 1535-7163
Seckl MJ, Roy R, Mauri F, et al., 2013, FGF-2 INDUCES CHEMORESISTANCE IN MODEL AND LUNG CANCER CELLS THROUGH S6K2/HNRNPA1-MEDIATED ENHANCED TRANSLATION OF ANTI-APOPTOTIC PROTEINS, JOURNAL OF THORACIC ONCOLOGY, Vol: 8, Pages: S1037-S1038, ISSN: 1556-0864
Tang H, Li H, Wang Y, et al., 2013, Combined preparation and application of combined preparation in preparing non-small-cell lung carcinoma drug, CN103330940A
The invention discloses a combined preparation and an application of the combined preparation in preparing a non-small-cell lung carcinoma drug. An EGFR (Epidermal Growth Factor Receptor) tyrosine kinase inhibitor and a preparation for increasing a concentration of glutathione (GSH) in lung carcinoma cells are administered simultaneously or successively. According to the combined preparation and the application, through a systemic research, the GSH plays an important role in resisting the EGFR tyrosine kinase inhibitor to an EGFR T790M mutation non-small-cell lung carcinoma, so that drug resisting cells are sensitive to treatment of the EGFR tyrosine kinase inhibitor again by utilizing a mode of increasing the concentration of the GSH in the lung carcinoma cells; and a cell experiment and an animal experiment prove that the method is safe and effective, can effectively kill the lung carcinoma cells, and can inhibit proliferation of the lung carcinoma cells.
Lara R, Seckl MJ, Pardo OE, 2013, The p90 RSK Family Members: Common Functions and Isoform Specificity, CANCER RESEARCH, Vol: 73, Pages: 5301-5308, ISSN: 0008-5472
- Author Web Link
- Citations: 79
Pardo OE, Seckl MJ, 2013, S6K2: The Neglected S6 Kinase Family Member., Frontiers in Oncology, Vol: 3, ISSN: 2234-943X
S6 kinase 2 (S6K2) is a member of the AGC kinases super-family. Its closest homolog, S6K1, has been extensively studied along the years. However, due to the belief in the community that the high degree of identity between these two isoforms would translate in essentially identical biological functions, S6K2 has been largely neglected. Nevertheless, recent research has clearly highlighted that these two proteins significantly differ in their roles in vitro as well as in vivo. These findings are significant to our understanding of S6 kinase signaling and the development of therapeutic strategies for several diseases including cancer. Here, we will focus on S6K2 and review the protein-protein interactions and specific substrates that determine the selective functions of this kinase.
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