Abstract
Small molecule inhibitors of signal transduction pathways can elicit complex and sometimes non-intuitive molecular responses in cancer cells. Increasing evidence supports the notion that these responses are important mediators of de novo drug resistance. We systematically assessed molecular and cellular responses to MEK inhibitors, aiming at identifying meaningful targets for combination therapies. Proteomic analyses revealed an EGFR-dependent feedback loop resulting in activation of the PI3 kinase pathway following MEK inhibition. In agreement with this, combinations of MEK inhibitors and inhibitors of EGFR inhibitors or PI3 kinase show synergistic effects on cell proliferation and apoptosis rates in molecularly defined disease subtypes. To further explore molecular networks affected by MEK inhibition, Bayesian network inference algorithms were applied and reverse-engineered networks were generated that are amenable to in silico forward-simulation. Using this technology, new, MEK-dependent, novel regulators of cell cycle and apoptosis were identified and experimentally validated. These findings highlight the potential of mathematical modeling approaches to efficiently reveal new and therapeutically relevant features of signal transduction networks.
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