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
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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