Imperial College London

Dr Olivier E. Pardo

Faculty of MedicineDepartment of Surgery & Cancer

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 2814o.pardo Website CV

 
 
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Location

 

145ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

55 results found

Li H, Stokes WB, Chater E, Rupniewska E, Roy R, Mauri FA, Liu X, Kaliszczak M, Downward J, Aboagye E, Tang H, Wang Y, Seckl MJ, Pardo OEet 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.

JOURNAL ARTICLE

Rupniewska E, Roy R, Mauri FA, Liu X, Kaliszczak M, Bellezza G, Cagini L, Barbareschi M, Ferrero S, Tommasi AM, Aboagye E, Seckl MJ, Pardo OEet 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.

JOURNAL ARTICLE

Poursaitidis I, Wang X, Crighton T, Labuschagne C, Mason D, Cramer SL, Triplett K, Roy R, Pardo OE, Seckl MJ, Rowlinson SW, Stone E, Lamb RFet 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

JOURNAL ARTICLE

Roy R, Huang Y, Seckl MJ, Pardo OEet al., 2017, Emerging roles of hnRNPA1 in modulating malignant transformation, WILEY INTERDISCIPLINARY REVIEWS-RNA, Vol: 8, ISSN: 1757-7004

JOURNAL ARTICLE

Li H, Stokes W, Chater E, Roy R, de Bruin E, Hu Y, Liu Z, Smit EF, Heynen GJJE, Downward J, Seckl MJ, Wang Y, Tang H, Pardo OEet 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

JOURNAL ARTICLE

Pardo OE, Castellano L, Munro CE, Hu Y, Mauri F, Krell J, Lara R, Pinho FG, Choudhury T, Frampton AE, Pellegrino L, Pshezhetskiy D, Wang Y, Waxman J, Seckl MJ, Stebbing Jet al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO REPORTS, Vol: 17, Pages: 570-584, ISSN: 1469-221X

JOURNAL ARTICLE

Pardo OE, 2015, Meningioma dissemination and growth: a role for microRNAs, ONCOGENE, Vol: 34, Pages: 1743-1744, ISSN: 0950-9232

JOURNAL ARTICLE

Schlegel CR, Georgiou ML, Misterek MB, Stoecker S, Chater ER, Munro CE, Pardo OE, Seckl MJ, Costa-Pereira APet al., 2015, DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function, CELL DEATH & DISEASE, Vol: 6, ISSN: 2041-4889

JOURNAL ARTICLE

Hoeland K, Boller D, Hagel C, Dolski S, Treszl A, Pardo OE, Cwiek P, Salm F, Leni Z, Shepherd PR, Styp-Rekowska B, Djonov V, von Bueren AO, Frei K, Arcaro Aet al., 2014, Targeting Class I-A PI3K Isoforms Selectively Impairs Cell Growth, Survival, and Migration in Glioblastoma, PLOS ONE, Vol: 9, ISSN: 1932-6203

JOURNAL ARTICLE

Pardo OE, Arcaro A, Salerno G, Tetley TD, Valovka T, Gout I, Seckl MJet 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

JOURNAL ARTICLE

Roy R, Durie D, Li H, Liu B-Q, Skehel JM, Mauri F, Cuorvo LV, Barbareschi M, Guo L, Holcik M, Seckl MJ, Pardo OEet 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

JOURNAL ARTICLE

Vincent EE, Elder DJE, O'Flaherty L, Pardo OE, Dzien P, Phillips L, Morgan C, Pawade J, May MT, Sohail M, Hetzel MR, Seckl MJ, Tavaré JMet 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.

JOURNAL ARTICLE

Kaliszczak M, Pardo OE, Seckl MJ, Aboagye EOet 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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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.

JOURNAL ARTICLE

Seckl MJ, Roy R, Mauri F, Hue L, Jordan L, Skehel M, Lin G, Holcik M, Pardo Oet 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

JOURNAL ARTICLE

Tang H, Li H, Wang Y, Pardo OE, Seckl MJet 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.

PATENT

Liwak U, Thakor N, Jordan LE, Roy R, Lewis SM, Pardo OE, Seckl M, Holcik Met 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

JOURNAL ARTICLE

De Laurentiis A, Pardo OE, Palamidessi A, Jackson SP, Schoenwaelder SM, Reichmann E, Scita G, Arcaro Aet 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

JOURNAL ARTICLE

Lara R, Mauri F, Taylor H, Derua R, Shia A, Gray C, Nicols A, Shiner RJ, Schofield EE, Bates P, Waelkens E, Dallman M, Lamb J, Zicha D, Downward J, Seckl M, Pardo Oet 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

JOURNAL ARTICLE

Lara R, Mauri FA, Taylor H, Derua R, Shia A, Gray C, Nicols A, Shiner RJ, Schofield E, Bates PA, Waelkens E, Dallman M, Lamb J, Zicha D, Downward J, Seckl MJ, Pardo OEet al., 2011, An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis, ONCOGENE, Vol: 30, Pages: 3513-3521, ISSN: 0950-9232

JOURNAL ARTICLE

Lara R, Mauri FA, Taylor H, Derua R, Shia A, Gray C, Nicols A, Shiner RJ, Schofield E, Bates PA, Waelkens E, Dallman M, Lamb J, Zicha D, Downward J, Seckl MJ, Pardo OEet al., 2011, An siRNA screen identifies Rsk1 as a key modulator of lung cancer metastasis, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472

JOURNAL ARTICLE

Rupniewska E, Mauri F, Watling D, Pardo O, Seckl Met 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

JOURNAL ARTICLE

Goh ETH, Pardo OE, Michael N, Niewiarowski A, Totty N, Volkova D, Tsaneva IR, Seckl MJ, Gout Iet 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

JOURNAL ARTICLE

Rupniewska E, Watling D, Mauri FA, Pardo OE, Seckl MJet 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

CONFERENCE PAPER

Lara R, Mauri F, Gray C, Nicols A, Schofield E, Bates P, Zicha D, Downward J, Seckl M, Pardo Oet al., 2009, An siRNA screen identifies RSK family members as key regulator of lung cancer metastasis, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472

JOURNAL ARTICLE

Marinov M, Ziogas A, Pardo OE, Tan LT, Dhillon T, Mauri FA, Lane HA, Lemoine NR, Zangemeister-Wittke U, Seckl MJ, Arcaro Aet 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

JOURNAL ARTICLE

Pardo OE, Latigo J, Jeffery RE, Nye E, Poulsom R, Spencer-Dene B, Lemoine NR, Stamp GW, Aboagye EO, Seckl MJet 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

JOURNAL ARTICLE

Seckl M, Pardo OE, Lara R, Mauri F, Bates P, Zicha D, Downward Jet 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

JOURNAL ARTICLE

Seckl MJ, Pardo OE, Aboagye EO, Latigo J, Stamp G, Lemoine N, Spencer-Dean Bet 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

JOURNAL ARTICLE

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