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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract 1857: Glioblastoma growth is suppressed dual inhibition of EGFR and CDK6 kinases
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1857-1857
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1857-1857
    Abstract: Glioblastoma (GBM) is a malignant brain tumor that has proven difficult to treat, despite expressing promising targets such as EGFRvIII. EGFRvIII, a mutant version of the epidermal growth factor receptor (EGFR), is constitutively active and not present in normal brain cells. The tumor specificity of EGFRvIII and the frequent EGFR amplification seen in GBM make EGFR a potentially attractive therapeutic target; however, clinical studies have shown little to no efficacy for EGFR tyrosine kinase inhibitors (TKI). One reason for this lack of efficacy may be adaptive resistance. We used RNA sequencing and multiplexed inhibitor beads with mass spectrometry (MIB-MS) to study the transcriptomes and kinomes of genetically engineered mouse astrocytes to investigate this resistance and identify potential targets for dual inhibition. Out of 329 kinases detected by MIB-MS, 76 were differentially expressed between cells with Cdkn2a deletion (“C”) and cells that also overexpressed EGFRvIII (“CEv3”). Thirty-four of these kinases were overexpressed in the CEv3 cells relative to the parental C cells (log2 fold change of 5.6, p & lt;1x105). One of these kinases, Cdk6, is also significantly overexpressed in CEv3 cells versus cells that have a further loss of function mutation of Pten (“CEv3P”) (log2 fold change of 5.6, p & lt;1x105). Despite this significant differential expression at the protein level, RNA expression of Cdk6 was similar between cell lines. When these cells were treated with the CDK6 inhibitor abemaciclib, CEv3 cells were found to be significantly more sensitive to inhibition than C and CEv3P cells (IC50 of 0.10 μM vs. 0.18 μM and 0.23 μM, respectively). Similarly, when cells were treated with abemaciclib in combination with the EGFR inhibitor neratinib, there was significantly higher synergy in CEv3 cells than C or CEv3P cells. Genotypically-matched patient-derived xenograft (PDX) cells were assayed for EGFR-CDK6 inhibitor synergy and showed a similar pattern of greater synergy in cells with EGFRvIII overexpression and functional PTEN than cells with EGFRvIII overexpression and PTEN loss. CEv3 and CEv3P cells were orthotopically implanted into mice and treated with neratinib, abemaciclib, or a combination. In CEv3-injected mice, combination treatment led to significantly longer survival than either single agent or control treatment. However, in CEv3P-injected mice, no survival difference was seen between any of the treatment arms. Taken together, these data provide strong evidence that CDK6 is a promising target for combination treatment with EGFR inhibitors in glioblastoma. Citation Format: Erin Smithberger, Abigail K. Shelton, Ryan E. Bash, Madison K. Butler, Alex R. Flores, Allie Stamper, Steven P. Angus, Michael P. East, Gary L. Johnson, Michael E. Berens, Frank B. Furnari, Ryan Miller. Glioblastoma growth is suppressed dual inhibition of EGFR and CDK6 kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1857.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1857
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
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  • 2
    Online Resource
    Online Resource
    Abstract 3019: Dynamic kinome profiling of EGFRvIII-driven murine astrocyte models of glioblastoma reveals targets for dual kinase inhibitor therapy
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3019-3019
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3019-3019
    Abstract: Glioblastoma (GBM) is an aggressive brain tumor with few effective treatments. Epidermal growth factor receptor (EGFR) is frequently amplified and mutated in GBM, leading to trials of several EGFR tyrosine kinase inhibitors, but none have proven successful. One potential reason for failure is acquired resistance, particularly acute, adaptive responses in the kinome. To study this adaptive resistance mechanism, we used RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze transcriptomes and kinomes of genetically-engineered murine astrocytes with genotypes commonly seen in human GBM. We previously showed that 38% (86 of 228) of the expressed kinome varied among a panel of genetically diverse murine astrocytes harboring Cdkn2a deletion (C) plus Pten deletion (CP), wild-type human EGFR (CE) or EGFRvIII (CEv3) overexpression, or both overexpressed EGFRvIII and Pten deletion (CEv3P). Pairwise genotype comparisons revealed multiple differentially activated kinases, including Pdgfrb, Fgfr2, Lyn, Ddr1, and several Ephrin family members. We further investigated these potential targets for dual therapy with EGFR TKI by examining the transcriptional response of cultured astrocytes at 4, 24, and 48 hours after 3 μM afatinib. Afatinib induced no kinome changes in C and only 3 kinases (Fn3k, Prkg2, and Syk) were altered in CP astrocytes. Despite similar baseline gene expression profiles, CE astrocytes overexpressing wild-type EGFR responded significantly differently than C astrocytes without. Five kinases (Dclk1, Epha3, Epha7, Fgfr3, and Prkg1) were induced, while 14 were repressed. Six were similarly repressed in CEv3 (Bub1, Nek2, Pask, Plk4, Prkcb, and Vrk1). Whereas the kinase transcriptome response was blunted in C, CP, and CE astrocytes, afatinib induced altered expression of significantly more kinases in CEv3 (82) and CEv3P cells (49). One particularly attractive target in CEv3 astrocytes was Epha4, which afatinib induced & gt;40-fold. Dual inhibition of EGFRvIII and Epha4 kinases may thus provide an opportunity for more effective targeted therapy. Citation Format: Erin Smithberger, Abigail K. Shelton, Madison K. Butler, Alex R. Flores, Ryan E. Bash, Steven P. Angus, Noah Sciaky, Harshil D. Dhruv, Gary L. Johnson, Michael E. Berens, Frank B. Furnari, C. Ryan Miller. Dynamic kinome profiling of EGFRvIII-driven murine astrocyte models of glioblastoma reveals targets for dual kinase inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3019.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3019
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 3
    Online Resource
    Online Resource
    Abstract LB-151: Positively selected enhancer elements endow tumor cells with metastatic competence
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-151-LB-151
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-151-LB-151
    Abstract: Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in signature enhancer-histone marks between near-isogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets is positively selected. Osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors whose motifs are enriched in Met-VELs, and by knockdown of individual genes activated by Met-VELs. These observations have implications for the discovery and development of targeted anti-metastatic therapies. Citation Format: James J. Morrow, Tyler E. Miller, Alina Saiakhova, Michael M. Lizardo, Cynthia F. Bartels, Ian Bayles, Stevephen Hung, Arnulfo Mendoza, Jay T. Myers, Frederick Allen, Analisa DiFeo, Brian P. Rubin, Alex Y. Huang, Paul S. Meltzer, Lee J. Helman, Chand Khanna, Peter C. Scacheri. Positively selected enhancer elements endow tumor cells with metastatic competence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-151.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-LB-151
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 4
    Online Resource
    Online Resource
    Abstract A13: Establishment and characterization of a panel of melanoma patient-derived xenograft (PDX) models.
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 11_Supplement ( 2013-11-01), p. A13-A13
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. A13-A13
    Abstract: Background: A majority of metastatic melanomas are driven by BRAF and NRAS mutations in the MAP/ERK kinase pathway. Recently approved therapies targeting B-Raf and Erk kinases have improved patient outcome; however, anticancer effects of these agents are transient, indicating additional pathways and mutations may play a role in disease progression. To better understand these mechanisms we have established a panel of melanoma patient-derived xenograft (PDX) models and characterized them by mutation, receptor and ligand density and drug sensitivity. Methods: PDX melanoma models were established in athymic nude mice from primary or metastatic patient tissue and once established were confirmed by histologic comparative analysis and linked with patient treatment and outcome data. For each model, DNA was extracted and subjected to exon sequencing of 207 known oncogenes; growth factor receptor and ligand densities were interrogated using immunohistochemistry and quantitative RNA in situ hybridization. Drug sensitivity studies were performed evaluating sensitivity of models towards chemotherapy and targeted agents including oral vemurafenib and trametinib. Vemurafenib was administered twice daily at 50 mg/kg and trametinib once daily at 1-3 mg/kg for at least twenty-eight days; oral temozolomide was tested at 100 mg/kg on a qdx5 schedule. Study endpoints included tumor volume and time from treatment initiation; with tumor growth inhibition, delay and regression reported at study completion. Results: BRAF mutations were identified in approximately 50% of melanoma models and 8% reported NRAS mutation; all identified mutations were concordant with clinical results reported from patients linked to the models. EGFR expression was reported in 13% of models (1+ to 3+) and HER3 expression (1+ to 3+) found in 55% of models with associated heregulin expression; HER2 was not found expressed in any evaluated melanoma model. Temozolomide tested at its maximum tolerated dose was ineffective in most models while vemurafenib was active in all evaluated B-RafV600E models and inactive in models with wildtype or alternate mutations. Trametinib was active in most B-RafV600E models and in some N-Ras-mutated models. Interestingly the ST054 model harboring B-RafL584 and N-RasQ61L mutations was sensitive to trametinib but not vemurafenib. Conclusion: We have established a panel of melanoma PDX models and characterized mutation status, receptor and ligand density and drug sensitivity. We found HER 3 expressed in a majority of models and benchmarked vemurafenib and trametinib activity in these models. This panel can be utilized as a valuable screening tool in early and late-stage oncology drug development. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A13. Citation Format: Lizette Gamez, Michael J. Wick, Teresa L. Vaught, Monica Farley, Anthony W. Tolcher, Drew Rasco, Amita Patnaik, Alex Miller, Ron Drengler, Kyriakos P. Papadopoulos. Establishment and characterization of a panel of melanoma patient-derived xenograft (PDX) models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A13.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-13-A13
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2062135-8
    detail.hit.zdb_id: 2063563-1
    SSG: 12
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