Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, the Netherlands
Chair of Proteomics and Bioanalytics, Technische Universitaet Muenchen, Freising, Germany
The small-molecule, ATP-competitive inhibitor Lapatinib is FDA approved for the treatment patients with advanced or metastatic breast cancer that overexpress HER2 and have been unsuccessfully treated with other therapies. Despite its clinical success, the downstream pathways are still not fully understood. In addition, most patients ultimately become resistant to the drug.
Our chemical proteomics selectivity screen against more than 200 protein kinases revealed that Lapatinib very selectively inhibits Her2 and EGFR, confirming the compounds narrow target spectrum. By combining chemical proteomic and phosphoproteomic data, new and known effectors were assigned to the Lapatinib response pathway based on the dose dependent change of activity regulating phosphorylation sites. Surprisingly, despite inhibitor treatment, several signaling molecules, for example members of the Src family of kinases, showed sustained and dose-dependent activation suggesting the release of feedback loops and the presence of adaptive resistance pathways. Moreover, from the data it seems that Lapatinib exerts its cytotoxic function at least in part by disruption of the protein translation. The cumulative experimental results were summarized and visualized within a pathway map providing a rich resource for further studies. Currently, follow up studies evaluating possible synergistic effects of drug combination treatments and protein knock-outs, based on the here identified signaling molecules, are performed.
Taken together, preliminary results show that the applied methods are complementary and identify known and new effectors of the cellular response to Lapatinib, providing a starting point for the rational and hypothesis driven evaluation of drug combination treatment.