Identification of tumour suppressor genes, whose loss mediates sensitivity to conventional chemotherapy and targeted therapeutics.
Progression to clinical trial is the ultimate goal of drug development. Selecting the appropriate patient populations is pivotal for the advancement to clinical setting. An innovative method of patient selection is to determine interactions between the drug being tested and known mutations in particular types of cancer. Presently there are many small molecule inhibitors undergoing clinical trials which use this concept. There is a wealth of literature surrounding the role of Src and Akt in tumour progression, invasion and metastasis and inhibitors of these kinases have become attractive drug targets. Aims: To identify tumour suppressor genes whose loss synergises with inhibition of Src and Akt. This would enable identification of a patient population who would benefit from these drugs in clinical studies. Methods: The effects of AZD0530 and MK2206 are investigated in HFF cells, reverse transfected with 178 siRNAs from a tumour suppressor library representative of all known tumour suppressor genes lost in cancer. Robust Z Scores determined potential sensitive hits and functional analysis of such hits were carried out through DAVID- a bioinformatics functional analysis website. Results: For HFF cells + siRNA treated with 5µM MK2206, 45 potential hits were identified as sensitive to this Akt Inhibitor, of which 2 were targeted by multiple siRNAs. For HFF cells + siRNA treated with AZD0530, 61 potential hits were identified as sensitive to this Src Inhibitor, of which 6 were targeted by multiple siRNAs. Discussion: This study aimed to identify potential biomarkers of response to inhibitors of Akt and Src, creating a patient population which would benefit from use of these agents. From the screen treated with AZD0530, two tumour suppressor genes arose- ERCC-1 and FANCD2; components of the Fanconi anaemia pathway. Loss or mutation of this pathway has the potential as a biomarker of response to Src Inhibitors clinically.