(351a) Elucidating the Effects of Drug Resistance Mechanisms in Tumours Via Multilevel Systems Modelling

Drug resistance plays an important role in  reducing the efficacy of chemotherapeutic treatment in tumours. In particular, an important challenge is to understand how these resistance mechanisms (primarily  intracellular based) affect the response of cancer cells to treatment, both at the single cell and tissue level. In order to do this, we first briefly outline a multilevel systems framework combining drug release, drug transport and cellular signalling. The cellular signalling is modelled with multiple levels of detail. This provides a platform to systematically elucidate effects of drugs on tumours.We then use this platform to elucidate the effects of different intracellular drug resistance mechanisms. One mechanism is via enhanced expression of P-glycoproteins, resulting in increased efflux of drug. A second mechanism is purely intracellular and is based on increased sequestration/metabolism of drugs.  We use our platform to elucidate the effects of these mechanisms both at the single cell and the tissue level, in response to different drug stimuli. We observe that different mechanisms which behave in similar ways at the single cell level can have very different tissue level behaviour. We also analyse the effects of combinations of such mechanism.Overall, the computational systems frameworks allows for multilevel elucidation and comparison of different resistance mechanisms in a systematic way.