Lampada, A; (2016) Targeting autophagy in colorectal cancer. Doctoral thesis , UCL (University College London).

Preview

Text Lampada_Thesis_Edited_combined_compressed.pdf Download (14MB) | Preview

Abstract

Alterations of metabolism have been implicated in cancer pathogenesis and response to therapy. Autophagy is a metabolic pathway providing the cell with intermediates of metabolism and limiting cellular damage via degradation of intracellular components in vesicular structures called autophagosomes/ autolysosomes. Basal autophagy plays a dual role in cancer: in normal tissues suppresses neoplastic transformation, whereas in established cancers sustains tumour growth. Therefore, it is important to evaluate the role of basal autophagy in CRC. Additionally, oncogenic tyrosine kinases (TKs) inhibit autophagy either directly, or indirectly via activation of the PI3K/mTOR pathway. Work from our group and others have shown that i) autophagy is induced upon TK-targeted therapeutics and ii) autophagy pharmacological inhibition increases sensitivity to TK targeted therapy. In colorectal cancer (CRC), which is the 3rd most common cancer type often characterised by PI3K and KRAS mutations, targeted inhibition of the Epithelial Growth Factor Receptor (EGFR) is used for the treatment of metastatic patients albeit with limited therapeutic benefit. It is presently unclear whether autophagy inhibition could potentiate EGFR targeted therapy in CRC. More generally, our knowledge on whether or how autophagy vice versa could control RTK activation is limited. The main aims of this research are: i) investigating the effect of EGFR inhibition on autophagy and the potential benefit of autophagy suppression in CRC; ii) exploring the role of basal autophagy in CRC and its relationship to signalling. I have shown that activating mutations in KRAS and PI3K genes make CRC cells resistant to EGFR inhibition as well as to autophagy induction, mainly through differential regulation of MAPK/ERK and PI3K/AKT pathways activation; thus suggesting that autophagy targeting would have limited impact in CRC. Conversely, PI3K mutant CRC cells display basal levels of autophagy despite the presence of constitutive PI3K/mTOR signalling and basal autophagy controls RTK activation and cell signalling. Finally, basal autophagy is suggested to play a tumour suppressive role under anchorage-independent cell growth conditions. Overall, these findings suggest a complex relationship between RTKs and autophagy: on one hand, autophagy activation upon RTK targeted therapy is dependent on PI3K mutational status; on the other hand, inhibition of basal autophagy affects RTK activation and downstream AKT and/or MAPK signalling independently of KRAS/PI3K mutations.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item