Influence of p53 family member activity on therapy resistance in malignant melanoma

点击翻译按钮获取中文摘要

The overall survival of melanoma patients with metastases has been greatly prolonged within the past few years due to new therapeutic strategies like kinase inhibitors for mutated BRAF or MEK and immune checkpoint blockers. However, rapidly emerging acquired resistance towards targeted therapies as well as the fact that not all patients respond to immunotherapy limit the clinical benefit of the therapies and revealed that there is a need for the development of alternative strategies to overcome resistance and non-responsiveness. In our previous work we showed that p53 activation reduces MAPK inhibitor resistance and influences the expression of the p53 homologue p73 in melanoma cells. We show that MAPK inhibitor resistant melanoma cells show enhanced sensitivity to DNA damage and we provide evidence that the TAp73 isoform is involved in mediating the enhanced sensitivity of these cells towards chemotherapeutic agents. The aim of this study is to elucidate the mechanism of the interplay of p53 and the TAp73 isoform in mediating therapy resistance towards MAPK inhibitors and DNA damaging drugs in melanoma cells. Within this project, we will analyze the mechanism of enhanced sensitivity of MAPK inhibitor resistant cells towards chemotherapy and the potential of alternating chemo- and MAPK inhibitor therapy as a novel therapeutic regimen for melanomas with acquired MAPK inhibitor resistance. Furthermore, since there is recent evidence that the p53/p73 axis is also involved in the immune cell response towards tumors, we will investigate the impact of targeting this signaling axis in order to antagonize melanoma immune escape.