Investigations on anti-IGF-1R therapy response in a colorectal cancer cell line panel

Thesis

Therapies targeting the type 1 insulin like growth factor receptor (IGF-1R) have so far failed to show significant benefit for colorectal cancer (CRC) patients in large clinical trials, emphasising the importance of identifying biomarkers for therapy response and developing rational combination therapies.

In this thesis, a large panel of 82 colorectal cancer cell lines was used to discover and validate associations between anti-IGF-1R therapy response, gene mutations and gene expression.

Mutations in PIK3CA exon 9 and 20 were found to be associated with resistance to inhibition with the tyrosine kinase inhibitor OSI-906 and the monoclonal antibody figitumumab. In a number of PIK3CA wild type cell lines, combination therapy with OSI-906 and the pan-Akt inhibitor GSK690693 yielded synergistic effects. PIK3CA wild type cell lines resistant to this combination therapy are characterised by KRAS mutations, a low expression of the cell surface protein CD24, and Akt-independent GSK-3β phosphorylation.

In summary, the findings of this thesis indicate an important role of the PI3K/Akt signalling pathway in anti-IGF-1R response in CRC. We have identified PIK3CA mutations as a biomarker for anti-IGF-1R therapy resistance in CRC. Furthermore, our study demonstrates a synergistic effect of the combination of OSI-906 with a pan-Akt inhibitor in a molecularly defined subgroup of CRC cell lines.

Authors: Puschhof, J

• DOI: 10.5287/ora-qmqnpvpy1
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: Targeted therapy; Cell line panel; IGF-1R; Colorectal cancer
• Subjects: Oncology; Drug research; Cell signalling