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

在过去几年中，由于新的治疗策略，如突变BRAF或MEK的激酶抑制剂和免疫检查点阻断剂，转移性黑色素瘤患者的总生存期大大延长。然而，对靶向疗法的快速出现的获得性耐药性以及并非所有患者对免疫疗法有反应的事实限制了疗法的临床益处，并揭示了需要开发替代策略来克服耐药性和无反应性。在我们以前的工作中，我们表明，p53激活降低MAPK抑制剂的耐药性，并影响黑色素瘤细胞中的p53同源物p73的表达。我们发现，MAPK抑制剂耐药的黑色素瘤细胞表现出增强的敏感性DNA损伤，我们提供的证据表明，TAp 73亚型参与介导这些细胞对化疗药物的敏感性增强。本研究的目的是阐明黑色素瘤细胞中p53和TAp 73亚型在介导对MAPK抑制剂和DNA损伤药物的治疗抗性中的相互作用的机制。在本项目中，我们将分析MAPK抑制剂耐药细胞对化疗敏感性增强的机制，以及交替化疗和MAPK抑制剂治疗作为获得性MAPK抑制剂耐药黑色素瘤的新治疗方案的潜力。此外，由于最近有证据表明，p53/p73轴也参与了对肿瘤的免疫细胞反应，我们将研究靶向这一信号传导轴的影响，以拮抗黑色素瘤免疫逃逸。

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.