55 results found
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.
Rupniewska E, Roy R, Mauri FA, et al., 2018, Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors., Oncotarget, Vol: 9, Pages: 27346-27362
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.
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
Roy R, Huang Y, Seckl MJ, et al., 2017, Emerging roles of hnRNPA1 in modulating malignant transformation, WILEY INTERDISCIPLINARY REVIEWS-RNA, Vol: 8, ISSN: 1757-7004
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
Pardo OE, Castellano L, Munro CE, et al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO REPORTS, Vol: 17, Pages: 570-584, ISSN: 1469-221X
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
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
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
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
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
BACKGROUND: Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC. METHODS: The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture. RESULTS: Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/β at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes. CONCLUSION: NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.
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
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
Pardo OE, Seckl MJ, 2013, S6K2: The Neglected S6 Kinase Family Member., Front Oncol, 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.
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.
Liwak U, Thakor N, Jordan LE, et al., 2012, Tumor Suppressor PDCD4 Represses Internal Ribosome Entry Site-Mediated Translation of Antiapoptotic Proteins and Is Regulated by S6 Kinase 2, MOLECULAR AND CELLULAR BIOLOGY, Vol: 32, Pages: 1818-1829, ISSN: 0270-7306
De Laurentiis A, Pardo OE, Palamidessi A, et al., 2011, The catalytic class I-A PI3K isoforms play divergent roles in breast cancer cell migration, CELLULAR SIGNALLING, Vol: 23, Pages: 529-541, ISSN: 0898-6568
Lara R, Mauri F, Taylor H, et al., 2011, IDENTIFICATION OF RSK1 AS A KEY MODULATOR OF LUNG CANCER METASTASIS, JOURNAL OF THORACIC ONCOLOGY, Vol: 6, Pages: S514-S515, ISSN: 1556-0864
Lara R, Mauri FA, Taylor H, et al., 2011, An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis, ONCOGENE, Vol: 30, Pages: 3513-3521, ISSN: 0950-9232
Lara R, Mauri FA, Taylor H, et al., 2011, An siRNA screen identifies Rsk1 as a key modulator of lung cancer metastasis, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Rupniewska E, Mauri F, Watling D, et al., 2011, ROLE OF SRC FAMILY KINASES IN NSCLC: AUTOPHAGY INHIBITORS POTENTIATE KILLING EFFECTS OF DASATINIB, JOURNAL OF THORACIC ONCOLOGY, Vol: 6, Pages: S744-S745, ISSN: 1556-0864
Goh ETH, Pardo OE, Michael N, et al., 2010, Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 285, Pages: 17065-17076, ISSN: 0021-9258
Rupniewska E, Watling D, Mauri FA, et al., 2010, Src family kinases in lung cancer, 21st Meeting of the European-Association-for-Cancer-Research, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 95-95, ISSN: 1359-6349
Lara R, Mauri F, Gray C, et al., 2009, An siRNA screen identifies RSK family members as key regulator of lung cancer metastasis, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472
Marinov M, Ziogas A, Pardo OE, et al., 2009, AKT/mTOR Pathway Activation and BCL-2 Family Proteins Modulate the Sensitivity of Human Small Cell Lung Cancer Cells to RAD001, CLINICAL CANCER RESEARCH, Vol: 15, Pages: 1277-1287, ISSN: 1078-0432
Pardo OE, Latigo J, Jeffery RE, et al., 2009, The Fibroblast Growth Factor Receptor Inhibitor PD173074 Blocks Small Cell Lung Cancer Growth In vitro and In vivo, CANCER RESEARCH, Vol: 69, Pages: 8645-8651, ISSN: 0008-5472
Seckl M, Pardo OE, Lara R, et al., 2009, RNAi library screen reveals RSK1 as a key regulator of lung cancer metastasis, JOURNAL OF THORACIC ONCOLOGY, Vol: 4, Pages: S559-S560, ISSN: 1556-0864
Seckl MJ, Pardo OE, Aboagye EO, et al., 2009, The FGF receptor (FGFR) inhibitor PD0173074 blocks SCLC growth in vitro and in vivo, JOURNAL OF THORACIC ONCOLOGY, Vol: 4, Pages: S385-S385, ISSN: 1556-0864
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.