Mechanism-based strategies to target oncogenic BRAF signaling
针对致癌 BRAF 信号传导的基于机制的策略
基本信息
- 批准号:9239071
- 负责人:
- 金额:$ 41.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-08 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse drug effectAdverse effectsAllosteric RegulationAllyAlpha CellAreaBRAF geneBindingBiochemicalBiological AssayCell LineCellsClinicalColorectalComplexDataDevelopmentDimerizationDrug DesignDrug resistanceEffectivenessEventGoalsHumanIn complete remissionInvestigationKnowledgeLinkMediatingModelingMolecular ConformationMulti-Drug ResistanceMutateMutationNormal CellOncogenicOutcomePatientsPharmaceutical PreparationsPharmacologyPropertyProto-Oncogene Proteins B-rafProtomerRas/RafRecoveryRegulationReportingResistanceResistance developmentSignal TransductionSiteTestingTherapeuticThyroid GlandTimeTreatment EfficacyWorkXenograft procedureacquired drug resistancebasebiophysical techniquescell growthclinical developmentclinical efficacycomparative efficacydesigndimereffective therapyexperimental studyimprovedin vivoinhibitor/antagonistinsightmelanomamutantnext generationpreclinical developmentresistance mechanismresponsesmall molecule inhibitortargeted treatmenttumor
项目摘要
Abstract
BRAF kinase is frequently found mutated in human tumors and in the majority of melanomas. RAF inhibitors
vemurafenib and dabrafenib improved survival of melanoma patients with BRAF(V600E) tumors. Unfortunate-
ly, responses are usually temporary, followed by development of resistance, most commonly due to ineffective
inhibition of RAF and reactivation of ERK signaling in the presence of the drug. In addition, RAF inhibitors in-
duce second site tumors, due to RAS-dependent paradoxical activation of RAF and downstream ERK signaling
in normal cells. Outside of melanoma, RAF inhibitors showed limited efficacy in patients colorectal and thyroid
BRAF(V600E) tumors, also due to ineffective inhibition of RAF/ERK signaling in these tumors. More recently,
combinations of RAF and MEK inhibitors showed improved efficacy compared to RAF inhibitor monotherapy,
but resistance eventually emerges as well. Resistance mechanisms identified to the RAF/MEK inhibitor combi-
nation are similar to the ones identified for RAF inhibitor monotherapy, suggesting that ineffective inhibition of
RAF is a critical limiting factor in both contexts. There is thus a pressing need for improved therapeutic strate-
gies targeting oncogenic BRAF, such that durable responses and minimal side effects can be achieved. Our
previous work showed that regulation of BRAF kinase by dimerization determines both the development of re-
sistance to currently used RAF inhibitors and inhibitor-induced RAF paradoxical activation, but the underlying
mechanisms remain incompletely understood. Recently, next generation RAF inhibitors with different structural
and biochemical properties have entered preclinical and clinical development, but the most appropriate clinical
context for their use is unknown. The goal of this proposal is to accomplish a detailed understanding of the
mechanisms governing the targeting of oncogenic BRAF by small molecules inhibitors and to use this
knowledge in order to design more effective RAF inhibitor-based therapeutic strategies. More specifically, we
will 1) characterize the mechanistic basis of resistance to RAF inhibitors due to BRAF dimerization by linking
the conformational changes induced by inhibitor binding to BRAF to the biochemical effects of the inhibitor, 2)
gain a detailed understanding of the biochemical mechanism of paradoxical RAF activation by inhibitors in cells
with wild-type BRAF and 3) identify effective RAF inhibitor-based therapeutic strategies for tumors with dimeric
BRAF that would overcome RAF dimer-mediated intrinsic or acquired resistance to RAF inhibitors. The mech-
anistic insights gained by the proposed experiments will enable the rational design of more effective small mol-
ecule inhibitors and RAF inhibitor-based therapeutic strategies targeting oncogenic BRAF signaling, with mini-
mal side effects and prolonged time to resistance.
摘要
BRAF激酶在人类肿瘤和大多数黑色素瘤中经常发现突变。RAF抑制剂
维莫拉非尼和达普拉非尼提高了患有BRAF(V600E)肿瘤的黑色素瘤患者的存活率。不幸的是-
LY,反应通常是暂时的,其次是抗药性的发展,最常见的原因是无效
在药物存在的情况下,抑制RAF和重新激活ERK信号。此外,RAF抑制剂在-
Ras依赖的RAF和下游ERK信号的矛盾激活所致的Duce第二部位肿瘤
在正常细胞中。除黑色素瘤外,RAF抑制剂对结直肠癌和甲状腺患者的疗效有限。
BRAF(V600E)肿瘤,也是由于在这些肿瘤中抑制RAF/ERK信号无效。最近,
与RAF抑制剂单一治疗相比,RAF和MEK抑制剂的联合治疗显示出更好的疗效。
但阻力最终也会出现。对RAF/MEK抑制剂联合耐药机制的研究
National类似于RAF抑制剂单一治疗的药物,表明抑制RAF无效
在这两种情况下,皇家空军都是一个关键的限制因素。因此,迫切需要改进治疗策略-
以致癌的BRAF为靶点的GES,因此可以实现持久的反应和最小的副作用。我们的
前人的工作表明,二聚化对BRAF激酶的调节既决定了BRAF-KK的发育,也决定了BRAF-KK的功能。
抵抗目前使用的RAF抑制剂和抑制剂诱导的RAF矛盾激活,但潜在的
机制仍然不完全清楚。近年来,具有不同结构的新一代RAF抑制剂
而生化特性已进入临床前和临床发展阶段,但临床上最合适
它们的使用环境尚不清楚。这项建议的目标是实现对
小分子抑制剂靶向致癌BRAF的机制及其应用
以设计更有效的RAF抑制剂为主的治疗策略。更具体地说,我们
将1)通过连接来表征由于BRAF二聚化而对RAF抑制剂产生抗性的机制基础
抑制剂与BRAF结合引起的构象变化对其生化效应的影响,2)
详细了解细胞内抑制物反常激活RAF的生化机制
与野生型BRAF和3)寻找有效的RAF抑制剂为基础的二聚体肿瘤的治疗策略
BRAF可克服RAF二聚体介导的对RAF抑制剂的固有或获得性耐药。机甲-
通过所提出的实验获得的反常的见解将使更有效的小分子分子的合理设计成为可能。
针对致癌的BRAF信号转导的基于ECULE抑制剂和RAF抑制剂的治疗策略,具有微型
不良反应和耐药时间延长。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Poulikos I Poulikakos其他文献
P-090: BRAF V600E multiple myeloma patient salvaged with triple MAPK inhibition after CAR T relapse
- DOI:
10.1016/s2152-2650(21)02224-2 - 发表时间:
2021-10-01 - 期刊:
- 影响因子:
- 作者:
Sarita Agte;Muhammad Elnaggar;Christos Adamopolous;David Melnekoff;Adolfo Adleman;Katerina Kappes;Paula Restrepo;Oliver Van Oekelen;Violetta Leshchenko;Poulikos I Poulikakos;Alessandro Lagana;Daniel Verina;Sundar Jagannath;Samir Parekh - 通讯作者:
Samir Parekh
Poulikos I Poulikakos的其他文献
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{{ truncateString('Poulikos I Poulikakos', 18)}}的其他基金
REGULATION AND ADAPTIVE MECHANISMS OF ONCOGENIC RAS/ERK SIGNALING
致癌 RAS/ERK 信号传导的调控和适应性机制
- 批准号:
10160858 - 财政年份:2020
- 资助金额:
$ 41.44万 - 项目类别:
REGULATION AND ADAPTIVE MECHANISMS OF ONCOGENIC RAS/ERK SIGNALING
致癌 RAS/ERK 信号传导的调控和适应性机制
- 批准号:
10381679 - 财政年份:2020
- 资助金额:
$ 41.44万 - 项目类别:
REGULATION AND ADAPTIVE MECHANISMS OF ONCOGENIC RAS/ERK SIGNALING
致癌 RAS/ERK 信号传导的调控和适应性机制
- 批准号:
10670052 - 财政年份:2020
- 资助金额:
$ 41.44万 - 项目类别:
Mechanism-based strategies to target oncogenic BRAF signaling
针对致癌 BRAF 信号传导的基于机制的策略
- 批准号:
10053708 - 财政年份:2016
- 资助金额:
$ 41.44万 - 项目类别:
Mechanism-based strategies to target oncogenic BRAF signaling
针对致癌 BRAF 信号传导的基于机制的策略
- 批准号:
9899477 - 财政年份:2016
- 资助金额:
$ 41.44万 - 项目类别:
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