Targeting of the Myc pathway as a novel approach for cancer therapy

Sammanfattning: As transcription factors, Myc-family proteins function upstream of signaling pathways and regulate cell proliferation, differentiation, angiogenesis, apoptosis and transformation. Precisely regulated Myc expression is critical for cellular physiology, while perturbations of Myc expression have detrimental consequences to the organism. First identified as the cellular homologue of a transforming gene of an avian retrovirus in 1979, deregulation of Myc was found to be closely related to many types of human cancers. Several studies using different animal models showed that activation of myc can induce tumor formation in various tissues. Interestingly, brief inactivation of myc results in tumor regression by inducing apoptosis, differentiation and/or dormancy of established tumors. These findings highlight the Myc pathway as an attractive target for tailored therapy for malignant tumors. For this purpose, we have established a cellular screening assay to identify small molecules that enhance cell death in Mycoverexpressing cells such as tumor cells, while having less effect on normal cells with lower Myc levels. Two identified small compounds, Myc pathway response agents-A (MYRA-A) and MYRAB, induced apoptosis in a Mycdependent manner and inhibited transformation driven by Myc. Our data showed that, although both compounds induce cell death in a similar manner, they act by different mechanisms. MYRA-A was found to work through interference with the DNA-binding of Myc family proteins and Myc-mediated transactivation, while the mechanisms of MYRA-B need to be elucidated. We have also characterized a third small molecule which showed prominent cellular toxicity to Myc-overexpressing cells and inhibited the DNA-binding of Myc proteins. In contrast to MYRAs, this compound (NSC408848) induced pan-inhibition of transactivation by several transcription factors. In parallel, we analyzed the relationship between Myc status and the effects of the anti-cancer drugs, camptothecin (CPT) and paclitaxel (PTX). We found that overexpression of Myc enhanced apoptosis induced by both drugs albeit through distinct mechanisms. Our data showed that CPT worked through inhibition of several transcription factors while the mechanisms for Myc-enhanced apoptosis by PTX needs is still unclear. Neither of the drugs affected the DNA-binding ability of Myc proteins. Moreover, we also found that PKCdelta was involved in CPTinduced apoptosis in the presence of Myc, while it seemed dispensable for the effect of PTX, regardless of Myc status. Our studies indicate that there are different possibilities to interfere with the Myc pathway in order to induce apoptosis specifically in cancer cells. Our work also suggests that cellular screening assays are powerful in identifying compounds that may be used as leads to develop novel cancer therapies.