Abstract

For a drug to effectively engage its intended target, it must be present at the correct concentration. In tumours, poor vascularity impacts drug availability. However, once at the tumour site, how drugs enter cancer cells is often overlooked. Drug development has aimed to optimise lipophilicity of compounds to ensure cell-permeability, but increasing evidence suggests that membrane transporters may also play an important role in drug uptake. In their endogenous role, transporters regulate the passage of metabolites across biological membranes and in cancer, their expression patterns are highly heterogeneous.

As well as trying to understand their role in cancer metabolism, we are interested in whether heterogeneity in transporter expression at the inter-patient level may contribute to patient-to-patient differences in therapeutic response. In support of this, we have evidence that several drugs reach distinct steady state concentrations in cell lines with different transporter expression signatures. At the intra-tumoural level, using mass spectrometry imaging of patient-derived tumour explant models, we have observed that drug uptake can also be heterogeneous, and we are exploring whether these spatial differences in drug uptake could be an under-explored mechanism of drug resistance.