Drivers of MAPK-redundant resistance to BRAF inhibition in melanoma

黑色素瘤中 MAPK 冗余对 BRAF 抑制产生耐药性的驱动因素

• 批准号: 10528454
• 负责人: Eliot Zhu
• 金额: $ 3.56万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528454
• 关键词: Actins; Address; BRAF gene; Biochemistry; Caring; Cell Line; Cells; Cessation of life; ChIP-seq; Classification; Complex; Cutaneous Melanoma; Drug resistance; Gene Expression Profile; Generations; Genetic; Genetic Screening; Genetic Transcription; Goals; Growth; Homo; Individual; Integrins; Knowledge; MAP Kinase Gene; MAP Kinase Modules; Malignant Neoplasms; Mediator; Medical Oncologist; Melanoma Cell; Mitogen-Activated Protein Kinases; Mutation; Oncogenic; Outcome; PDGFRB gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Protein Family; Proteins; Recurrence; Reporting; Research; Resistance; Signal Transduction; Skin Cancer; Sleeping Beauty; System; Testing; Transcription Factor AP-1; Work; acquired drug resistance; dimer; drug resistance development; effective therapy; genetic manipulation; genome-wide; improved; in vitro Assay; in vivo; inhibitor; inhibitor therapy; insight; melanoma; member; mutant; next generation; novel; pharmacologic; programs; raf Kinases; resistance mechanism; therapeutic target; therapy development; transcription factor; transcriptional reprogramming; transcriptome; transcriptome sequencing; transcriptomic profiling; transcriptomics; treatment strategy

PROJECT SUMMARY Cutaneous melanoma is an aggressive form of skin cancer. In the US alone, approximately 90,000 new cases and 9,000 deaths due to melanoma were reported in 2017. Selective inhibitors of BRAFV600E/K work potently against melanomas driven by oncogenic BRAF. Unfortunately, drug resistance is ubiquitous, and most patients will progress within two years of therapy. Large-scale genome- and transcriptome- profiling reveal that resistance to MAPK inhibition (MAPKi) is either MAPK- dependent or redundant. MAPK-dependent (resistance ~50%) resistance is characterized by the reactivation of MAPK typically through mutations that augment MAPK signaling. These MAPKi-resistant melanomas are nearly identical at the transcriptome level to their respective parental cancers, which further support these cancers simply restore MAPK. By contrast, MAPK-redundant resistance (remaining 50%) is characterized by extensive transcriptional reprogramming and is often devoid of recurrent mutations. Mechanistically, MAPK-dependent resistance is centered on the formation of Raf homo- or heter- dimers that are resistant to current generation Raf inhibitors but sensitive to next-generation Raf inhibitors that have dimer activity. However, MAPK-redundant resistance is not uniform, not well-understood, and lacks a common therapeutic target. This knowledge is important as there are no current treatment options for melanomas with MAPK-redundant resistance. To address this critical gap, we performed a forward genetic screen to identify novel mechanisms that drive resistance to MAPKi. This screen was performed using our well-established Sleeping Beauty Transposon system. The outcome of this screen was that SFKs and PDGFRβ were the preferred MAPK-redundant mechanisms of resistance for BRAFV600E melanomas A375 and SKMEL28. However the precise mechanisms by which SFKs and PDGFRβ drive MAPK-redundant resistance are unknown. In Aim 1, I will elucidate the mechanism of SFKs- and PDGFRβ- driven resistance to MAPKi by testing the hypothesis that actin remodeling is central to MAPKi resistance that is driven by both SFKs or PDGFRβ and that integrins are critical upstream of the SFKs resistance program and Akt is a critical downstream meditator of the PDGFR resistance program. In Aim 2 I will test the hypothesis that SFKs and PDGFRβ promotes MAPKi resistance by activating the Yap/Taz/TEAD/AP-1 transcriptional complex. The central hypothesis is that actin remodeling and the YAP/TAZ/AP-1 complex are critical mediators of the SFKs- and PDGFRβ- resistance programs.

项目摘要 皮肤黑色素瘤是皮肤癌的一种侵略性形式。仅在美国，大约有90,000个新案件 2017年报道了由于黑色素瘤而导致的9,000例死亡。 反对由致癌BRAF驱动的黑色素瘤。不幸的是，耐药性无处不在，大多数患者 将在治疗两年内进展。大规模基因组和转录组分析表明，抗性 对MAPK抑制（MAPKI）是MAPK依赖性或冗余。 MAPK依赖性（电阻〜50％） 电阻的特征是MAPK通常通过增强MAPK的突变重新激活 信号。这些抗MAPKI的黑色素瘤在转录组级别几乎与它们各自相同 父母癌症，进一步支持这些癌症只是还原MAPK。相比之下，MAPK冗余 电阻（剩余50％）的特征是传统的转录重编程，并且通常没有 复发突变。从机械上讲，MAPK依赖性电阻以Raf homo-或homo-或 对当前一代RAF抑制剂具有抗性但对下一代RAF抑制剂敏感的异二聚体 具有二聚体活动。但是，MAPK冗余的抵抗并不统一，并不理解，并且缺乏 共同的理论目标。这些知识很重要，因为目前没有治疗选择 MELOMA具有MAPK冗余电阻。 为了解决这个关键的差距 驱动对MAPKI的阻力。此屏幕是使用我们成熟的睡美人Transposon进行的 系统。该屏幕的结果是SFK和PDGFRβ是首选的MAPK冗余 BRAFV600E黑色素瘤A375和SKMEL28的抗性机制。但是，精确的机制是 哪些SFK和PDGFRβ驱动MAPK冗余电阻尚不清楚。在AIM 1中，我将阐明 通过测试肌动蛋白重塑的假设，SFKS和PDGFRβ驱动对MAPKI的抗性机制 是由SFK或PDGFRβ驱动的MAPKI抗性的核心，整联蛋白是关键的上游 SFKS电阻程序和AKT是PDGFR阻力程序的关键下游冥想者。在 AIM 2我将检验以下假设：SFK和PDGFRβ通过激活 yap/taz/tead/ap-1转录复合物。中心假设是肌动蛋白的重塑和 YAP/TAZ/AP-1复合物是SFKS和PDGFRβ-抗性程序的关键介体。

项目成果

SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas.

• DOI: 10.1038/s41698-022-00310-7
• 发表时间: 2022-10-21
• 期刊: NPJ PRECISION ONCOLOGY
• 影响因子: 7.9
• 作者: Zhu, Eliot Y.;Riordan, Jesse D.;Vanneste, Marion;Henry, Michael D.;Stipp, Christopher S.;Dupuy, Adam J.
• 通讯作者: Dupuy, Adam J.