Targeting MARK2-HDAC signaling to overcome paclitaxel resistance in pancreatic cancer
靶向 MARK2-HDAC 信号传导以克服胰腺癌中的紫杉醇耐药性
基本信息
- 批准号:10707545
- 负责人:
- 金额:$ 26.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-20 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAlbuminsAnimal ModelAnimalsBindingBiochemicalCancer EtiologyCellsCellular biologyCessation of lifeChemoresistanceChromosomal InstabilityClinicClinicalClinical TrialsCombined Modality TherapyDataDrug resistanceFDA approvedGenesGeneticGenetic EpistasisGenetic TranscriptionGoalsGrowthHDAC4 geneHistone DeacetylaseHistone Deacetylase InhibitorImmuneImmunocompetentIn VitroKPC modelMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMalignant neoplasm of pancreasMapsMediatingMetabolismMethodsMicrotubulesMitoticMolecularOutcomePaclitaxelPancreatic Ductal AdenocarcinomaPathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPhosphorylation SitePhosphotransferasesPrognostic MarkerProteinsRecurrenceRegulationResistanceRoleSerineSignal PathwaySignal TransductionSurvival RateTestingTextTherapeuticTranscription CoactivatorTranslatingTreatment outcomeTubulinUnited StatesVorinostatantitumor agentcancer cellcancer therapycancer typecell growthchemotherapycytotoxicitydrug sensitivityefficacy outcomesgemcitabinehistone deacetylase 2improvedin vivomalignant breast neoplasmmortalitynanoparticlenovelpancreatic cancer patientspancreatic ductal adenocarcinoma cellpatient derived xenograft modelpatient responsepre-clinicalprogramsresponsetherapeutic targetupstream kinase
项目摘要
Abstract Text
Many antitubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of several types
of cancer, including breast, ovarian, lung, and pancreatic cancers. Despite their wide use in cancer treatment,
however, patient response is highly variable and drug resistance remains a major clinical issue. It is therefore
essential to identify prognostic markers to predict the patient response and to enhance drug sensitivity.
Through biochemical and cell-based kinome-wide screens, we identified MARK2 (microtubule affinity-
regulating kinase 2) as a critical regulator for Taxol chemosensitivity in PDAC (pancreatic ductal
adenocarcinoma) cells. We show that MARK2 is phosphorylated in response to antitubulin chemotherapeutics.
We further identified the corresponding kinase and mapped phosphorylation sites. MARK2 determines Taxol
cytotoxicity in PDAC cells without affecting growth under normal conditions. Mechanistically, our findings also
suggest that MARK2 controls Taxol chemosensitivity by regulating class IIa HDACs (histone deacetylase).
MARK2 directly phosphorylates HDAC4 upon Taxol treatment. MARK2-phosphorylated HDAC4 positively
regulates YAP (yes-associated protein) activity and controls expression of YAP target genes specifically
induced by Taxol. Inhibition of HDACs sensitizes PDAC cells to Taxol treatment in vitro and in
immunocompetent animals. Our hypothesis is that the MARK2-HDACs axis functions as a therapeutic target
for overcoming Taxol resistance in PDAC patients. We will test our central hypothesis by three specific aims.
Aim 1: Determine the role and regulation of MARK2 in response to antitubulin chemotherapeutics; Aim 2:
Elucidate the downstream effectors and mechanisms of MARK2 in response to Taxol chemotherapeutics; Aim
3: Targeting HDACs and serine metabolism to overcome Taxol resistance in PDAC. The identification of new
regulators and/or signaling pathways triggered by antitubulin drugs will shed light on the mechanisms
underlying chemoresistance. Our study suggests that combining HDAC inhibitors with antitubulin agents (e.g.
Taxol) will have enhanced efficacy in treatment of drug-resistant and/or recurrent PDAC patients.
抽象的文字
项目成果
期刊论文数量(0)
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Jixin Dong其他文献
Jixin Dong的其他文献
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{{ truncateString('Jixin Dong', 18)}}的其他基金
Targeting MARK2-HDAC signaling to overcome paclitaxel resistance in pancreatic cancer
靶向 MARK2-HDAC 信号传导以克服胰腺癌中的紫杉醇耐药性
- 批准号:
10518249 - 财政年份:2022
- 资助金额:
$ 26.1万 - 项目类别:
Targeting PKR-Bcl2 Signaling to Overcome Paclitaxel Resistance in Ovarian Cancer
靶向 PKR-Bcl2 信号传导以克服卵巢癌中的紫杉醇耐药性
- 批准号:
10502982 - 财政年份:2022
- 资助金额:
$ 26.1万 - 项目类别:
Targeting PKR-Bcl2 Signaling to Overcome Paclitaxel Resistance in Ovarian Cancer
靶向 PKR-Bcl2 信号传导以克服卵巢癌中的紫杉醇耐药性
- 批准号:
10672464 - 财政年份:2022
- 资助金额:
$ 26.1万 - 项目类别:
Regulation and Functional Dissection of YAP in Mitosis
YAP 在有丝分裂中的调控和功能解析
- 批准号:
8614249 - 财政年份:2014
- 资助金额:
$ 26.1万 - 项目类别:
Regulation and Functional Dissection of YAP in Mitosis
YAP 在有丝分裂中的调控和功能解析
- 批准号:
8790759 - 财政年份:2014
- 资助金额:
$ 26.1万 - 项目类别:
REGULATION AND FUNCTION OF KIBRA IN THE HIPPO SIGNALING PATHWAY
KIBRA 在 HIPPO 信号通路中的调节和功能
- 批准号:
8360441 - 财政年份:2011
- 资助金额:
$ 26.1万 - 项目类别:
REGULATION AND FUNCTION OF KIBRA IN THE HIPPO SIGNALING PATHWAY
KIBRA 在 HIPPO 信号通路中的调节和功能
- 批准号:
8168390 - 财政年份:2010
- 资助金额:
$ 26.1万 - 项目类别:
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