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  • 1
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    Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice
    Springer Science and Business Media LLC ; 2017
    In:  Nature Communications Vol. 8, No. 1 ( 2017-02-21)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2017-02-21)
    Abstract: Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/ncomms14572
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
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  • 2
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    Suppression of HER2/HER3-Mediated Growth of Breast Cancer Cells with Combinations of GDC-0941 PI3K Inhibitor, Trastuzumab, and Pertuzumab
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 12 ( 2009-06-15), p. 4147-4156
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 12 ( 2009-06-15), p. 4147-4156
    Abstract: Purpose: Oncogenic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is prevalent in breast cancer and has been associated with resistance to HER2 inhibitors in the clinic. We therefore investigated the combinatorial activity of GDC-0941, a novel class I PI3K inhibitor, with standard-of-care therapies for HER2-amplified breast cancer. Experimental Design: Three-dimensional laminin-rich extracellular matrix cultures of human breast cancer cells were utilized to provide a physiologically relevant approach to analyze the efficacy and molecular mechanism of combination therapies ex vivo. Combination studies were done using GDC-0941 with trastuzumab (Herceptin), pertuzumab, lapatinib (Tykerb), and docetaxel, the principal therapeutic agents that are either approved or being evaluated for treatment of early HER2-positive breast cancer. Results: Significant GDC-0941 activity (EC50 & lt;1 μmol/L) was observed for & gt;70% of breast cancer cell lines that were examined in three-dimensional laminin-rich extracellular matrix culture. Differential responsiveness to GDC-0941 as a single agent was observed for luminal breast cancer cells upon stimulation with the HER3 ligand, heregulin. Combined treatment of GDC-0941, trastuzumab, and pertuzumab resulted in growth inhibition, altered acinar morphology, and suppression of AKT mitogen-activated protein kinase (MAPK) / extracellular signed-regulated kinase (ERK) kinase and MEK effector signaling pathways for HER2-amplified cells in both normal and heregulin-supplemented media. The GDC-0941 and lapatinib combination further showed that inhibition of HER2 activity was essential for maximum combinatorial efficacy. PI3K inhibition also rendered HER2-amplified BT-474M1 cells and tumor xenografts more sensitive to docetaxel. Conclusions: GDC-0941 is efficacious in preclinical models of breast cancer. The addition of GDC-0941 to HER2-directed treatment could augment clinical benefit in breast cancer patients.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-2814
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 3
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    Abstract B14: Inherent resistance to BRAF inhibitors in BRAFV600E colorectal tumors is driven by ligand-dependent activation of the EGFR pathway
    American Association for Cancer Research (AACR) ; 2012
    In:  Clinical Cancer Research Vol. 18, No. 10_Supplement ( 2012-05-15), p. B14-B14
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 10_Supplement ( 2012-05-15), p. B14-B14
    Abstract: Constitutive activation of the RAS, RAF, mitogen-activated protein kinase (MEK), and extracellular signal regulated kinase (ERK) pathway drives tumor cell proliferation and survival in many cancer types, and activating mutations in KRAS or BRAF occur in over 30% of human tumors. It has been demonstrated that BRAF inhibitors are effective selectively against BRAFV600E tumors and not RAS mutant tumors, despite BRAF functioning as a key effector downstream of RAS and upstream of MEK. Recent Phase I clinical data with RAF inhibitors has demonstrated a significant response rate (81%) in metastatic melanoma patients with BRAFV600E-positive tumors (N Engl J Med. 2010;363:809–19). Interestingly, in contrast to this remarkable response in melanoma, the response rates in BRAFV600E-positive colon tumors have been low in comparison (5.2%) (Kopetz et al., ASCO 2010). It has recently been reported that elevated EGFR levels in a subset of BRAFV600E lines render them resistant to BRAFV600E selective inhibitors (Prahallad et al., Nature. 2012; Corcoran et al., Cancer Discovery. 2012). However, the kinetics of EGFR pathway activation in response to inhibitors and underlying mechanisms of resistance are not entirely clear. In this study, we demonstrate that BRAFV600E/EGFR high tumors show a biphasic response to BRAF inhibitors, whereby the MAPK pathway is effectively blocked upon acute treatment, but subsequently rebounds and becomes resistant to inhibition. Components of the negative feedback loop downstream of the MAPK pathway including Sprouty, MKP3, and CDC25C are downregulated during acute treatment but rebound upon prolonged treatment, coincident with phospho-ERK suppression and subsequent reactivation. We show that this effect is not only dependent on high EGFR levels but also requires EGFR ligand stimulation that can be mediated through autocrine signaling. Resistance to this pathway is associated with increased RAS-GTP levels driving wild-type RAF activation upon extended treatment with B-RAF inhibitors. Importantly, immunohistochemical staining of tissue microarrays representative of both BRAFWT and BRAFV600E mutant CRC tumors with an EGFR antibody illustrates that the BRAFV600E mutation in colorectal cancer is associated with a significantly higher percentage of tumors carrying membrane EGFR compared to BRAFWT CRC tumors, with the median of membrane EGFR positive cells in BRAFV600E tumors 56.5% vs. 15% of cells in BRAFWT tumors, suggesting that activation of both pathways may be required for tumorigenesis in this tissue type. Finally, using both in vitro and in vivo models, we demonstrate that, in BRAFV600E-positive colon tumors with high EGFR pathway activity, inherent resistance to BRAF-selective inhibitors can be overcome by combination treatment with clinically relevant inhibitors of EGFR signaling, providing a potential treatment strategy for BRAFV600E/ EGFR high tumors. In summary, these results provide mechanistic insight into the crosstalk between BRAFV600E and EGFR signaling in CRC, shed light into the low response rate of BRAFV600E mutant colorectal cancer to BRAF inhibitors as single agents, and provide a rationale for the use of BRAF and EGFR inhibitors as combination therapy in this indication.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.MECHRES-B14
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 4
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    GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 12 ( 2011-12-01), p. 2426-2436
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 12 ( 2011-12-01), p. 2426-2436
    Abstract: Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic. Mol Cancer Ther; 10(12); 2426–36. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-11-0446
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 5
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    Abstract A250: Preclinical combination efficacy and identification of biomarkers of MEK and PI3K inhibitors in phase I
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. A250-A250
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. A250-A250
    Abstract: Introduction: The Raf/MEK/ERK and PI3K/Akt/mTOR pathways are two major effector pathways downstream of activated Ras and receptor tyrosine kinases. While Ras is an attractive cancer target, direct pharmacological targeting has so far been unsuccessful. We describe preclinical studies combining GDC-0973, an inhibitor of MEK, and GDC-0941, an inhibitor of PI3K, both of which are in Phase I trials. Summary of Results: GDC-0973 is a selective allosteric orally bioavailable small molecule inhibitor of the MEK1/2 dual specificity kinases. It has nanomolar potency against MEK1/2 in cells, and has potency across a broad range of cancer cell lines, most notably in those that are mutated for B-Raf and K-Ras. GDC-0941 is a selective orally bioavailable small molecule inhibitor of Class I PI3 kinases that has been described previously. Given the widespread and frequently concurrent activation of the Ras/Raf/MEK and Ras/PI3K/Akt pathways in tumors such as melanoma, colorectal, non-small cell lung cancer, and pancreatic cancer, we carried out cellular and in vivo xenograft studies to evaluate the efficacy of GDC-0973 and GDC-0941, both individually and in combination. We demonstrate strong combination efficacy in B-raf or K-ras mutant melanoma, colon and NSCLC models, driven primarily by increased apoptosis. The combination resulted in modulation of markers of both the MEK and PI3K pathways, and we discovered several markers whose modulation correlated with the induction of apoptosis. Continuous suppression of the two pathways is not required for combination efficacy. Conclusions: The preclinical data indicate that combined use of MEK and PI3K inhibitors can produce greater efficacy than either agent alone at tolerated doses. Additionally, biomarkers have been identified which correlate with induction of apoptosis in the combination regimens. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A250.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-A250
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
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  • 6
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    Abstract B90: Understanding the effects of RAF inhibitors on RAF signaling in B-RAF V600E mutant versus wild type tumors
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. B90-B90
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B90-B90
    Abstract: Constitutive activation of the Ras, RAF, mitogen-activated protein kinase (MEK), and extracellular signal regulated kinase (ERK) pathway is a common finding in many human cancers. Activating mutations in K-Ras or B-RAF constitute over 30% of all mutations in human tumors. Therefore, identifying therapeutic strategies to downregulate this pathway could have broad therapeutic impact. It has been demonstrated that RAF inhibitors selectively inhibit B-RAFV600E tumors and not Ras mutant tumors, despite functioning as one of the key effector enzymes downstream of Ras and upstream of MEK. In this work we demonstrate that although RAF inhibitors effectively inhibit phospho-MEK and phospho-ERK levels in B-RAFV600E cells, pathway induction is observed for RAF inhibitors in B-RAF WT/K-Ras Mutant or B-RAF WT/K-Ras WT cell lines as evidenced by increases in phospho-MEK, phospho-ERK and phospho-p90RSK levels. We also show that with increasing concentrations of RAF inhibitors, the downstream pathway can be inhibited in WT B-RAF and mutant K-Ras cell lines. Stimulation of the pathway with growth factors or serum can attenuate phospho-MEK and phospho-ERK induction upon treatment with RAF inhibitors. Additionally, mechanistic studies demonstrate that RAF inhibitors can directly activate RAF kinase activity. Taken together, our data suggests that RAF inhibitors may have opposing functions as both activators and inhibitors of the MAPK pathway, depending on cellular context. These results provide new insight into the therapeutic utility of MAPK pathway inhibitors, and emphasize the importance of correlating target occupancy with pharmacodynamic markers of efficacy, and of targeting defined genetic backgrounds in cancer treatment. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B90.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-B90
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
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  • 7
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    Abstract C201: A novel potent and selective inhibitor of PI3K/mTOR, GDC-0980, currently in phase I clinical trials
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. C201-C201
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. C201-C201
    Abstract: Introduction: The phosphoinositide-3 kinase (PI3K)/Akt signaling pathway is deregulated in a wide variety of cancers. Somatic activating mutations and amplifications in PI3K are common in multiple cancers including breast, colon, and lung cancer. PTEN, a phosphatase that converts PIP3 to PIP2 and thus has an opposing function to PI3K, is a commonly mutated tumor suppressor in multiple cancers including prostate and glioblastoma. Alterations of this pathway have been implicated in tumor initiation, progression, survival, angiogenesis, and metastasis. PI3K/Akt pathway activation has also been implicated in therapeutic resistance. Thus PI3K is considered to be a promising therapeutic target for cancer. Summary of Results: Medicinal chemistry efforts resulted in the discovery of GDC-0980, a selective, orally bioavailable inhibitor of PI3 Kinase and mTOR kinase with promising pharmacokinetic and pharmaceutical properties. Here we report the first pre-clinical profile of GDC-0980. This compound is a potent ATP-competitive Class I PI3 kinase inhibitor with an IC50 of 4.8 nM against the PI3K p110apha subunit, 26.8 nM p110beta, 6.7 nM p110delta, 13.8 nM p110gamma, and an mTOR Kiapp of 17.3 nM. GDC-0980 demonstrates selectivity against a large panel of protein kinases as well as selectivity over PIK family kinases including Class II, Class III, and DNA-PK. GDC-0980 inhibits the PI3K signaling pathway in vitro causing a reversible G1 cell cycle arrest, and apoptosis induction in a subset of tumor cell lines. Levels of signaling pathway markers such as phosphorylated AKT (pAKT), PRAS40 (pPRAS40), and S6 (pS6) are rapidly and dramatically reduced following exposure of cells to GDC-0980. Oral dosing of GDC-0980 potently inhibits tumor growth in xenograft models including those mutated in PI3K and PTEN, and elicits an exposure-related concomitant decrease in PD biomarkers. Conclusion: These preclinical data provide compelling evidence in support of GDC-0980 as a clinical candidate, and Phase I studies are ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C201.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-C201
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 8
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    Abstract 349: PI3K inhibitor GDC-0941 synergizes with mTOR inhibitors by blocking negative feedback and causes distinct effects on signaling and apoptosis compared to a dual PI3K/mTOR inhibitor
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 349-349
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 349-349
    Abstract: Background: The PI3K/Akt/mTOR pathway is deregulated in many cancers. and activation of Akt leads to the stimulation of cell survival and proliferation pathways. Akt activation also regulates mTOR to control cell growth in response to growth factors and nutrients. The PI3K pathway is therefore an attractive target for cancer therapy. Multiple targeted inhibitors of PI3K, mTOR and PI3K/mTOR are currently in clinical trials, whileTORC1 inhibitors including rapamycin and analogs are approved. In this study we assessed the consequence of the combination of a PI3K inhibitor, GDC-0941, plus a TORC1 or TORC1/2 inhibitor compared to dual PI3K/mTOR inhibitor, in cancer cell lines with different genetic backgrounds. Method: We analyzed the effects of PI3K, TORC1 or TORC1/2 inhibition alone or in combination on the viability, cell cycle profile and apoptosis of cancer cell lines with varying PI3K, PTEN, K-ras, and LKB status. Effects on signaling were analyzed by measuring the phosphorylation of signaling proteins by reverse phase protein array and other techniques. Effects on viability and apoptosis were assessed, along with a calculation of synergy for combinations. Results: Inhibition of PI3K with GDC-0941 or a dual PI3K/mTOR inhibitor inhibited proliferation of cancer cell lines and in certain tumor lines induced apoptosis. Treatment also resulted in the inactivation of downstream markers including pAKT, pPRAS40 and pS6. TORC1/2 inhibition resulted in a potent inhibition of pS6, however it had differential effects on phospho-AKT and survival proteins pBad and pGSK3b, likely due to the release of the negative feedback regulation. The signaling effects demonstrated by TORC1/2 inhibition also differed from TORC1 inhibition by rapamycin. Inhibition of mTOR resulted in a cytostatic response in all lines tested. Combination of PI3K and mTOR inhibitors (either TORC1 or TORC1/2) caused a significant decrease in cell viability, enhanced apoptosis and caused a greater, sustained knockdown of the signaling pathway. However, treatment with a dual PI3K/mTOR inhibitor led to slight but consistently lower levels of apoptosis than the combination of the separate agents. There were also differences in phosphoprotein status of some of the pathway components. Conclusion: Inhibiting multiple nodes within the same signaling pathway is synergistic and can be an effective strategy to enhance potency in cancer cells. However, combinations of selective targeted agents do not necessarily cause identical effects as a single molecule that inhibit multiple targets simultaneously. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 349.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-349
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 9
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    Abstract DDT02-03: Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. DDT02-03-DDT02-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. DDT02-03-DDT02-03
    Abstract: The extracellular-signal-regulated kinases (ERK1 and ERK2) represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that commonly is activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling, such as receptor tyrosine kinase (RTK) activation. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Here, we present the discovery and characterization of GDC-0994, an orally bioavailable, small molecule inhibitor of ERK kinase activity. GDC-0994 is highly selective for ERK1 and ERK2, with biochemical potency of 1.1 nM and 0.3 nM, respectively. Daily, oral dosing of GDC-0994 results in significant single-agent activity in multiple in vivo cancer models, including KRAS-mutant and BRAF-mutant human xenograft tumors in mice. PD biomarker inhibition of phospho-p90RSK in these tumors correlates with potency in vitro and in vivo. In contrast to other published ERK inhibitors, GDC-0994 neither increases nor decreases phospho-ERK, suggesting that different ERK inhibitors have alternative mechanisms of action with respect to feedback signaling. Furthermore, we demonstrate a novel approach for targeting the oncogenic signaling through the RAS pathway by combining ERK and MEK inhibitors. GDC-0994 is currently in Phase I clinical development. Citation Format: Kirk Robarge, Jacob Schwarz, Jim Blake, Michael Burkard, Jocelyn Chan, Huifen Chen, Kang-Jye Chou, Dolores Diaz, John Gaudino, Stephen Gould, Jonas Grina, Xin Linghu, Lichuan Liu, Matthew Martinson, David A. Moreno, Christine Orr, Patricia Pacheco, Ann Qin, Kevin Rasor, Li Ren, Sheerin Shahidi-Latham, Jeffrey Stults, Francis Sullivan, Weiru Wang, Peter Yin, Aihe Zhou, Marcia Belvin, Mark Merchant, John G. Moffat. Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT02-03. doi:10.1158/1538-7445.AM2014-DDT02-03
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-DDT02-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 10
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    Abstract 2340: Preferential targeting of KRAS mutant or BRAF mutant tumors using MEK inhibitors with distinct mechanisms of action.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2340-2340
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2340-2340
    Abstract: KRAS and BRAF mutant cancers represent an area of high unmet medical need in oncology. Multiple allosteric MEK inhibitors are being tested in clinical trials in BRAF mutant and KRAS mutant cancers, where to date they have demonstrated impressive single agent activity in BRAF mutant melanoma, but not in KRAS mutant disease. Active, phosphorylated MEK is elevated in BRAFV600E mutant melanoma tumor models compared to KRAS mutant tumor models, in line with evidence that MAPK pathway regulation differs depending on the upstream oncogenic lesion. However, the precise differences in MEK activation by mutant KRAS or BRAF and how to create MEK inhibitors to block that activation are not known. In this study we describe two clinical, allosteric MEK inhibitors, GDC-0973 and GDC-0623, that have complementary efficacy profiles, with one showing superior efficacy in BRAF mutant models and the other showing superior efficacy in KRAS mutant models. Using structural information and targeted mutagenesis, we demonstrate that although both inhibitors effectively block MEK kinase activity and downstream ERK activation, their unique binding modes result in differential effects on active versus inactive MEK and MEK interaction with RAF that translates into unique efficacy profiles in BRAFV600E versus KRAS mutant tumors. GDC-0973 has already shown promising efficacy as a single agent in BRAFV600E mutant melanoma, and both inhibitors are currently being tested in KRAS mutant tumors in the clinic. Our study highlights that subtle differences in the binding mode of kinase inhibitors can have a large impact on inhibitor/target interactions and efficacy through allosteric mechanisms. These differences may impact the therapeutic index of MEK inhibitors in either BRAF mutant or KRAS mutant cancers. Citation Format: Georgia Hatzivassiliou, Jacob Haling, Huifen Chen, Kyung Song, Shiuh-Ming Luoh, Steve Price, Robert Heald, Mark Zak, Mark Merchant, Klaus Hoeflich, Lori Friedman, Shiva Malek, Marcia P. Belvin. Preferential targeting of KRAS mutant or BRAF mutant tumors using MEK inhibitors with distinct mechanisms of action. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2340. doi:10.1158/1538-7445.AM2013-2340
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2340
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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