Proteomics of Colorectal Cancer Liver Metastasis: a Quantitative Focus on Drug Elimination and Pharmacodynamics Effects.

Aim This study aims to quantify drug-metabolising enzymes (DMEs), transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal, and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. Methods Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time (AMRT) LC-MS proteomics were used to quantify proteins. A QconCAT ('KinCAT') for the quantification of RTKs was designed and applied for the first time. Physiologically-based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of DMEs and transporters to changes in pharmacokinetics. Results Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54-fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13-fold) drug clearance when using cancer-specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76-fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over-expression of such pathways. Conclusion This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population-specific abundance data in PBPK models for cancer.