更新于：2024-11-01

WEE1 x SRC

更新于：2024-11-01

基本信息

关联

项与 WEE1 x SRC 相关的药物

PD-0166285

靶点

SRC x WEE1

作用机制

SRC抑制剂 [+1]

在研机构

Parke-Davis & Co. Ltd. [+1]

原研机构

Pfizer Inc.

在研适应症

动脉粥样硬化 [+3]

非在研适应症

血管再狭窄

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 WEE1 x SRC 相关的临床结果

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100 项与 WEE1 x SRC 相关的转化医学

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0 项与 WEE1 x SRC 相关的专利（医药）

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项与 WEE1 x SRC 相关的文献（医药）

2021-11-01·Journal of Biological Chemistry

The KRAS-regulated kinome identifies WEE1 and ERK coinhibition as a potential therapeutic strategy in KRAS-mutant pancreatic cancer

Article

作者: Baldelli, Elisa ; Hodge, Richard G ; Snare, Kayla R ; Petricoin, Emanuel F ; Cox, Adrienne D ; Yang, Runying ; Papke, Björn ; Blake, Devon R ; Klomp, Jennifer E ; Rashid, Naim U ; Gilbert, Thomas S K ; Hibshman, Priya S ; Herring, Laura E ; Graves, Lee M ; Pierobon, Mariaelena ; Kaiser, Zane D ; Diehl, J Nathaniel ; Der, Channing J

Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines and then applied multiplexed inhibitor bead/MS to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transformation and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS. We identified 15 upregulated and 13 downregulated kinases in common across the panel of cell lines. In agreement with our hypothesis, all 15 of the upregulated kinases have established roles as cancer drivers (e.g., SRC, TGF-β1, ILK), and pharmacological inhibition of one of these upregulated kinases, DDR1, suppressed PDAC growth. Interestingly, 11 of the 13 downregulated kinases have established driver roles in cell cycle progression, particularly in mitosis (e.g., WEE1, Aurora A, PLK1). Consistent with a crucial role for the downregulated kinases in promoting KRAS-driven proliferation, we found that pharmacological inhibition of WEE1 also suppressed PDAC growth. The unexpected paradoxical activation of ERK upon WEE1 inhibition led us to inhibit both WEE1 and ERK concurrently, which caused further potent growth suppression and enhanced apoptotic death compared with WEE1 inhibition alone. We conclude that system-wide delineation of the KRAS-regulated kinome can identify potential therapeutic targets for KRAS-mutant pancreatic cancer.

2021-09-01·Gastric Cancer1区 · 医学

WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers

1区 · 医学

Article

作者: Jin, Mei-Hua ; Kim, Tae-Yong ; Seo, Hye-Rim ; Bang, Ju-Hee ; Nam, Ah-Rong ; Oh, Kyoung-Seok ; Oh, Do-Youn ; Yoon, Jeesun ; Kim, Jae-Min

BACKGROUNDTo date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance.METHODSIn our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773).RESULTSHere, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro.CONCLUSIONTaken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.

2016-01-02·Expert Opinion on Investigational Drugs2区 · 医学

An overview of tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer

2区 · 医学

Review

作者: Wang, Zhijie ; Fu, Siqing

INTRODUCTIONEpithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most common cause of cancer-related deaths in women. Initial treatment with surgery and chemotherapy has improved survival significantly. However, the disease progresses or recurs in most patients. Thus, there is an urgent need to develop more effective treatment strategies.AREAS COVEREDThis article provides an overview of tyrosine kinase inhibitors (TKIs) for the treatment of EOC, which is based on English peer-reviewed articles on MEDLINE and related abstracts presented at major conferences. The authors highlight the data from the published clinical trials in EOC patients who were treated with TKIs or TKI-based regimens.EXPERT OPINIONEOC is responsive to most chemotherapeutic drugs and/or biological agents and represents an ideal disease model for investigating novel anti-cancer agents. Numerous small-molecule TKIs targeting the VEGFR, PARP, PI3K-AKT-mTOR, MAPK, Src, PKC, Wee1 and HER1/2 signaling pathways are currently being tested in clinical trials. Research is needed for devising regimens combining TKIs with other agents in an optimal timing schedule and for identifying potential biomarkers predictive of response and survival.