Gamma-secretase inhibition combined with platinum compounds enhances cell death in a large subset of colorectal cancer cells

63 CRC lines contained a fragment with approximately the size of the Notch1 intracellular domain (NICD), which is required for signalling. Subsequent analyses with an antibody that specifically recognises the free Val1744 residue generated by γ-secretase-mediated cleavage of Notch1 showed that a subset of CRC cells lacks this specific Val1744-NICD. Surprisingly, inhibition of Val1744-NICD signalling with different γ-secretase inhibitors (GSI) did not lead to substantial effects on CRC cell line growth or survival. However, transient activation of Erk upon GSI treatment was detected. Since cisplatin relies on Erk activation for bioactivity in some cells, platinum compounds were tested together with GSI and enhanced cell killing in a subset of Val1744-NICD-positive CRC cell lines was detected. Erk inhibition ablated this combination effect.We conclude that γ-secretase inhibition results in activation of the MAP kinases Erk1/2 and, when used in conjunction, enhances cell death induced by platinum compounds in a large subset of colorectal cancer cell lines.Furthermore the activation of Erk appears to be of particular importance in mediating the enhanced effect seen, as its inhibition abrogates the observed phenomenon. These findings do not only highlight the importance of signalling pathway crosstalk but they may also suggest a new avenue of combination therapy for some colorectal cancers.The Notch signalling pathway, already discovered in 1919 by Thomas H. Morgan in the fruit fly Drosophila melanogaster, plays numerous roles in organismal development and tissue homeostasis as well as in different cancers [1-5]. For the activation of Notch signalling, a number of proteolytic processing events are required, most notably the final cleavage of Notch1 by a multi-protein complex termed γ-secretase. This releases a defined fragment (Val1744-NICD) of the membrane bound Notch protein into the cytoplasm, from where it translocates into the nucleus and subsequently mediates the t