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

p53家族成员活性对恶性黑色素瘤治疗耐药的影响

• 批准号: 392228267
• 负责人: Professorin Dr. Birgit Schittek
• 金额: --
• 依托单位: Sektion Dermatologische Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392228267?language=en
• 关键词: Influence; p53; family; member; activity

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.

在过去的几年中，由于新的治疗策略，如针对突变BRAF或MEK的激酶抑制剂和免疫检查点阻滞剂，黑色素瘤转移患者的总体生存期大大延长。然而，迅速出现的对靶向治疗的获得性耐药性以及并非所有患者对免疫治疗有反应的事实限制了治疗的临床益处，并表明需要开发替代策略来克服耐药性和无反应性。在我们之前的工作中，我们发现p53激活降低了MAPK抑制剂的耐药性，并影响了黑色素瘤细胞中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对DNA损伤的敏感性增强，我们提供的证据表明，TAp73异构体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p53和TAp73异构体在介导黑色素瘤细胞对MAPK抑制剂和DNA损伤药物的治疗耐药中的相互作用机制。在这个项目中，我们将分析MAPK抑制剂耐药细胞对化疗敏感性增强的机制，以及化疗和MAPK抑制剂交替治疗作为获得性MAPK抑制剂耐药的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轴也参与免疫细胞对肿瘤的反应，我们将研究靶向该信号轴以拮抗黑色素瘤免疫逃逸的影响。