Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713361
Title: Targeting PI3K pathway to enhance cisplatin cytotoxicity in lung cancer models
Author: Liao, Wenjing
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2017
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Abstract:
Lung cancer is a leading cause of cancer deaths and is commonly diagnosed in both males and females. The cause of lung cancer is mainly attributable to cigarette smoking and aging, accounting for more than half of all lung cancer deaths. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer (about 80%) compared to small cell lung cancer (SCLC) and it is normally subclassified into squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Cisplatin-based treatments are the main first-line regimens for any stage of NSCLC, although platinum has over a 40-year history of use in clinical practice. Recently, molecularly targeted agents have been developed for improvement of treatment outcomes in patients with advanced lung cancers, such as EGFR-and ALK-targeted drugs. However, the acquired resistance to these agents eventually impairs sensitivity to treatment. Studies have shown that PI3K/Akt signaling activation is associated with resistance to the targeted treatments, and highlights a role for targeting PI3K/Akt signaling to restore sensitivity to targeted therapies. Moreover, Akt inhibition has been shown to promote sensitivity to cisplatin treatment. In this project, both cisplatin and various agents which target Akt directly or indirectly, were tested on 2D NSCLC cell cultures for assessment of potencies. Single-agent treatment showed that the mutant P53 cell line (H596) showed the greatest sensitivity to cisplatin treatment compared to two WT P53 cell lines (A549 and H460). This was similarly observed in a patient-derived tissue explant model which showed that P53 mutant cases were more sensitive to cisplatin treatment than those WT P53 cases. In 2D adherent cell culture and 3D organotypic co-culture of cancer cells with fibroblasts, Akt activity was activated in response to cisplatin treatment, which was similarly observed in one explant case. Moreover, decreased Akt phosphorylation was significantly correlated with increased PARP cleavage in WT P53 cases only. Both PI3K- and Akt-targeted treatments were shown to be highly potent on 2D culture and 3D spheroid models compared to other cisplatin-based regimens. Further analysis of molecular biomarkers by In-Cell western assay corroborated this, with induction of caspase-3-dependent cell death significantly higher when cisplatin treatment was combined with PI3K- or Akt-targeting drugs. The increase in apoptosis was concurrently observed with decreases in pAkt levels. P53 and PTEN levels were not induced by combination treatments compared to cisplatin alone, suggesting that functional P53 might not be required for induction of cell death.
Supervisor: Howells, Lynne ; Brown, Karen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.713361  DOI: Not available
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