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Elucidating Novel Akt Regulatory Mechanisms to Overcome Akt-mediated Therapeutic Resistance in Breast Cancer

阐明新的 Akt 调节机制以克服 Akt 介导的乳腺癌治疗耐药性

基本信息

批准号：
10054188
负责人：
Wenjian Gan
金额：
$ 24.9万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054188
关键词：
Ablation American Award BRCT Domain Basic Cancer Research Binding Biochemistry Biological Assay Biological Models Biological Process Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy CDK4 gene Cancer Etiology Cell Culture System Cell Culture Techniques Cells Cessation of life Chemoresistance Clinical Combination Drug Therapy Complex Cyclin D1 DNA Damage DNA Sequence Alteration DNA-dependent protein kinase Data Development Doxorubicin Drug Targeting Drug resistance Family Future Genetic Goals In Vitro Knowledge Malignant Neoplasms Mediating Molecular Multi-Drug Resistance Oncogenic Outcome PDPK1 gene Pathway interactions Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Play Problem Solving Reader Relapse Research Research Training Resistance Role Scientist Serine Signal Pathway Signal Transduction Specificity Therapeutic Transgenic Mice Treatment outcome Tumor Suppressor Proteins Woman Xenograft Model Xenograft procedure attenuation breast tumorigenesis cancer diagnosis career career development chemotherapeutic agent chemotherapy clinical Diagnosis design experimental study hormone therapy improved in vivo inhibitor/antagonist malignant breast neoplasm mouse model novel prevent response therapy resistant transcription factor tumor

项目摘要

Abstract: Hyper-activation of the Akt kinase and oncogenic function is a hallmark of breast cancer and has been shown to be tightly associated with chemotherapy and hormone therapy resistance, leading to a worse clinical outcome in breast cancer patients. Although substantial progress has been made in the past decades to understand the molecular mechanisms of Akt activation, our knowledge about the upstream signaling pathways controlling Akt kinase activity is far from complete that restrain us from targeting the Akt oncogenic signaling pathway for treating breast cancers. Accumulating evidence has shown that Akt can be activated by DNA damage or in Rb-deficient cells. However, the molecular mechanisms underlying Akt activation in either DNA damage or Rb-deficient conditions are largely unknown. The goal of this proposal is to uncover the molecular mechanisms underlying how the upstream signaling pathways, such as DNA-PK and Rb, regulate Akt to confer chemotherapy resistance in breast cancer, as well as to examine whether Akt inhibitors could synergize with DNA damage drugs or CDK4/6 inhibitors to suppress Akt signaling and overcome drugs resistance. To this end, in Aim 1, our preliminary data showed that during DNA damage response, DNA-PK- mediated Sin1 phosphorylation is required for DNA damage-induced Akt activation. We will further define the molecular mechanisms through which Sin1 phosphorylation by DNA-PK governs Akt activation under DNA damage condition. We will also determine whether synergistic usage of DNA damaging drugs and Akt inhibitors could more efficiently suppress breast cancer in both cell culture and mouse model systems. In Aim 2, we have obtained preliminary evidence to demonstrate that the Rb tumor suppressor inhibits Akt kinase activity largely through directly binding Sin1. Although Rb exerts its tumor suppressor role through suppressing E2F family of transcriptional factors, we will investigate the molecular mechanisms underlying the non- canonical tumor suppressive role of Rb in inhibiting Sin1 (mTORC2)-mediated activation of Akt. Moreover, we will examine whether inhibiting Rb phosphorylation would activate Akt to confer therapeutic drugs resistance, and determine whether Akt inhibitors would sensitize breast cancer cells to CDK4/6 inhibitors in vitro and in vivo. Therefore, the proposed studies will not only define a novel Sin1-dependent Akt activation mechanism, but also provide the rationale and molecular basis for the synergistic usage of chemotherapeutic drugs or CDK4/6 with Akt inhibitors clinically to overcome drugs resistance. My research career goals are to apply the biochemistry, cellular culture and mouse models to understand how the aberrant cancer signaling pathways contribute to breast cancer development and relapse, and to explore possible drug targets to achieve better clinical outcomes for breast cancer therapy. This K99/R00 award will allow me to improve my ability to design and execute experiments as well as solve problems. Moreover, this award will also facilitate my research career development through independently conducting scientific research and training future young scientists.

文摘:

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair.

DOI：
10.1126/scisignal.aar8133
发表时间：
2018-06-05
期刊：
Science signaling
影响因子：
7.3
作者：
Liu P;Gan W;Su S;Hauenstein AV;Fu TM;Brasher B;Schwerdtfeger C;Liang AC;Xu M;Wei W
通讯作者：
Wei W

Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation.

DOI：
10.1016/j.canlet.2016.10.021
发表时间：
2017-01-28
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Wu, Fei;Dai, Bxiangpeng;Gan, Wenjian;Wan, Lixin;Li, Min;Mitsiades, Nicholas;Wei, Wenyi;Ding, Qiang;Zhang, Jinfang
通讯作者：
Zhang, Jinfang

PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis.

DOI：
10.1038/s41467-021-23833-2
发表时间：
2021-06-08
期刊：
Nature communications
影响因子：
16.6
作者：
Yin S;Liu L;Brobbey C;Palanisamy V;Ball LE;Olsen SK;Ostrowski MC;Gan W
通讯作者：
Gan W

Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt.

DOI：
10.1016/j.molcel.2016.04.023
发表时间：
2016-06-16
期刊：
Molecular cell
影响因子：
16
作者：
Zhang J;Xu K;Liu P;Geng Y;Wang B;Gan W;Guo J;Wu F;Chin YR;Berrios C;Lien EC;Toker A;DeCaprio JA;Sicinski P;Wei W
通讯作者：
Wei W

The Roles of Post-Translational Modifications on mTOR Signaling.