Predicting and Overcoming Drug Resistance

The development of drug resistance is a major and as it seems inevitable obstacle in cancer therapy. Drug resistance can be caused by many mechanisms, most prominently the overexpression and activation of transporters that pump drugs out of the target cells, and the acquisition and selection of mutations that obliterate drug efficacy. Only recently, the structural design of signalling networks and the emergent properties that derive from that design have been recognised as mechansims of drug resistance.

For instance, the Ras-Raf-MEK-ERK pathway is altered in >30% of all human cancers. Recently, the analysis of this pathway by mathematical modelling and concomitant experimentation revealed that this pathway has properties of a negative feedback amplifier (Sturm et al., 2010; PMID: 21180766), which convey robustness against perturbations of the amplifier, in this case drugs that target MEK which is part of the amplifier module.

These results may explain why MEK inhibitors so far have failed in the clinic despite high potency and selectivity in vitro. More importantly, the computational model made the unexpected prediction that Raf inhbitors should synergize with MEK inhibitors, which indeed was the case (Sturm et al., 2010; PMID: 21180766). This non-obvious prediction has in the meantime been independently confirmed and is being evaluated for clinical application (Poulikakos and Solit, 2011; PMID: 21447797).