Translational proteomics to understand and overcome drug resistance to targeted anticancer drugs in KRAS and PIK3CA driven cancers

Translational proteomics to understand and overcome drug resistance to targeted anticancer drugs in KRAS and PIK3CA driven cancers Background Cancer results in over 160,000 deaths per year and accounts for more than 25% of all deaths in the UK. Recent advances in molecularly targeted agents, in large part kinase inhibitors, have resulted in significant benefit in defined clinical contexts; however, large areas of unmet medical need remain. There are no targeted anticancer drugs used specifically in common cancers with known oncogenic mutations; for example, non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and breast cancers which harbour KRAS or PIK3CA mutations and these cancers have de-novo resistance to many targeted drugs. In addition, cancers that do respond eventually develop resistance, a phenomenon called acquired resistance. It is becoming evident that there is a varied clinical response when targeted anticancer agents are used to treat tumours driven by common oncogenes, depending on the tissue of origin of the cancer. Thus, understanding drug resistance and finding strategies to overcome this is an area of urgent unmet need. Overall objectives To use primary tumour samples derived from patients, combined with the application of emerging technology, to understand the mechanisms of drug resistance caused by re-wiring of signalling and dynamic changes in protein levels within cancer cells. This information will be used to guide rational combinations strategies of targeted anticancer drugs. To understand the contribution of tissue context in drug resistance to targeted anticancer drugs, which is critical in the development of anticancer drugs and in the design of future clinical trials. Methods The project will optimize existing tissue digestion protocols to extract cancer cells from tumours. Barcoded antibody technology on the NanoString platform has recently been commercialised and the project will use the technology to develop an assay allowing the measurement of 100 phosphoprotein/proteins exposed to 25 drugs from a single biopsy or surgical specimen. The information related to quantifying re-wiring of signalling within cancer cells will be analysed as part of existing collaborations with bioinformaticians at The Institute of Cancer Research to understand mechanisms of resistance and propose rational combinations of anticancer drugs to overcome this resistance. Differences in rewiring of KRAS mutant CRC, PDAC and NSCLC cells and PIK3CA mutant breast, NSCLC and CRC cells when exposed to a range of 25 targeted anticancer agents will be studied and any correlation to differences in sensitivity to targeted anticancer drugs will be established. KRAS mutant CRC, PDAC and NSCLC will be co-cultured with and without cancer associated fibroblasts to study the influence of stroma on re-wiring of signal transduction in response to anticancer drugs. Information from these experiments will be used to design clinical trials of rational combinations of anticancer drugs in specific tumour types. Impact on patients and the NHS This proposal will lead to improved understanding of the mechanisms of resistance of common KRAS-driven cancers. Importantly, the work will help devise rational combination therapies that can be tested in hypothesis-testing clinical trials within a period of 3 - 5 years. The information related to context specificity of drug resistance in different tumour types e.g. NSCLC, PDAC and CRC will further help to tailor clinical trials of combinations in these tumour types. The outcomes of these clinical trials conducted within the Experimental Cancer Medicine Centre (ECMC) at The Institute of Cancer Research and The Royal Marsden, and The National Institute of Health Research (NIHR) will improve the outcomes of patients with common mutant KRAS- and PIK3CA-driven cancers, which are areas of high unmet need.