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  • American Association for Cancer Research (AACR)  (2)
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  • American Association for Cancer Research (AACR)  (2)
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  • 1
    Online Resource
    Online Resource
    Functional Characterization of an Isoform-Selective Inhibitor of PI3K-p110β as a Potential Anticancer Agent
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Discovery Vol. 2, No. 5 ( 2012-05-01), p. 425-433
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 2, No. 5 ( 2012-05-01), p. 425-433
    Abstract: Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms. Significance: We report the first functional characterization of a p110β-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient human tumors. Cancer Discov; 2(5); 425–33. ©2012 AACR. Read the Commentary on this article by Shepherd and Denny, p. 393. This article is highlighted in the In This Issue feature, p. 377.
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-12-0003
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2607892-2
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 337: p16INK4A-deficiency predicts for response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 337-337
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 337-337
    Abstract: Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). To identify predictors of response and resistance to brain-penetrant, small molecule targeted therapies, we performed whole exome sequencing, RNAseq and quantitative immunohistochemistry of HER2+ BCBM tissues from 21 patients. We found that the tumor suppressor p16INK4A (p16) was deficient in the majority of HER2+ BCBMs. Orthotopic HER2+ BCBM patient-derived xenograft (PDX) models with p16 deficiency were resistant to the brain-penetrant HER2 inhibitor, tucatinib or the brain penetrant CDK4/6 inhibitor, abemaciclib, when used as single agents. However, p16-deficiency predicted response to combined tucatinib and abemaciclib in orthotopic HER2+ BCBM PDX models. These data establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2+ BCBM. Citation Format: Jing Ni, Sheheryar Kabraji, Shaozhen Xie, Yanzhi Wang, Peichen Pan, Xiaofang He, Zongming Liu, Henry Long, Myles Brown, Eric P. Winer, Deborah Dillon, Nancy Lin, Jean Zhao. p16INK4A-deficiency predicts for response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 337.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-337
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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