16 Matching Annotations
  1. Last 7 days
  2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Untitled document
    16
    1. karim2001khoury 19 Feb 2026
      PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells

      [Paper-level Aggregated] PMCID: PMC2848976

      Evidence Type(s): Predictive, Oncogenic, Functional

      Justification: Predictive: The study demonstrates that the presence of BRAF mutations, specifically BRAFV600E/K, predicts sensitivity to the drug PLX4032, as evidenced by the significantly lower IC50 values in BRAF mutant melanoma cell strains compared to BRAF wild-type cells. Oncogenic: The BRAFV600E/K mutations are described as frequent mutationally active tumor-specific kinases in melanomas, indicating their role in driving oncogenesis in these tumors. Functional: The study explores the functional effects of PLX4032 on ERK1/2 phosphorylation and downstream signaling pathways, demonstrating how BRAF mutations influence cellular responses to the drug.

      Gene→Variant (gene-first): BRAF(673):BRAFV600E BRAF(673):BRAFV600K NRAS(4893):Q61L BRAF(673):V600E/K JUNB(3726):R89L BRAF(673):V600E

      Genes: BRAF(673) NRAS(4893) JUNB(3726)

      Variants: BRAFV600E BRAFV600K Q61L V600E/K R89L V600E

      CIViC paper-level aggregated PMC2848976
    2. karim2001khoury 19 Feb 2026
      BRAFV600E/K is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells that are BRAFV600E/K and BR

      [Paragraph-level] PMCID: PMC2848976 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Predictive, Oncogenic, Functional

      Justification: Predictive: The passage discusses how BRAFV600E/K is targeted for therapy with the specific inhibitor PLX4032, indicating a correlation with treatment response. Oncogenic: BRAFV600E/K is described as a mutationally active tumor-specific kinase in melanomas, suggesting its role in tumor development or progression. Functional: The passage mentions that PLX4032 alters the activity of ERK1/2 in BRAFV600E/K cells, indicating a change in molecular function related to the variant.

      Gene→Variant (gene-first): 673:BRAFV600E 4893:Q61L 673:V600E/K

      Genes: 673 4893

      Variants: BRAFV600E Q61L V600E/K

      CIViC paragraph-level PMC2848976 Predictive Oncogenic Functional
    3. karim2001khoury 19 Feb 2026
      Two additional assays confirmed that activated FAK had a functional impact on BRAFWT melanoma cells. First, there was a dramatic reduction in colony formation in soft agar in response to PLX4032 (Figure 6C), although the

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 24

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how activated FAK has a functional impact on BRAFWT melanoma cells, specifically noting changes in colony formation and cell motility in response to PLX4032, indicating alterations in molecular or biochemical function. Oncogenic: The mention of BRAFWT and BRAFV600E in the context of melanoma cells suggests that these variants are involved in tumor behavior, particularly in how they respond to treatment and their migratory capabilities, indicating a role in tumor development or progression.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976 Functional Oncogenic
    4. karim2001khoury 19 Feb 2026
      PLX4032 also had physiological effects on advanced melanoma cells. We observed enhanced detachment of BRAFWT melanoma cells after treatment with PLX4032 for several hours that were 99% viable (Figure 6A). In contrast, th

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 23

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effects of PLX4032 on melanoma cells, indicating a difference in response between BRAFWT and BRAFV600E cells, which suggests a correlation with treatment response. Oncogenic: The mention of BRAFV600E in the context of advanced melanoma cells implies that this somatic variant contributes to tumor development or progression, as it is associated with specific cellular behaviors in the study.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976 Predictive Oncogenic
    5. karim2001khoury 19 Feb 2026
      One of the main questions raised by our studies is whether ERK activation had any impact on cellular functions, because we did not detect a significant increase in the proliferation rate of advanced BRAFWT melanoma cells

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 21

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 4893:Q61L

      Genes: 4893

      Variants: Q61L

      CIViC paragraph-level PMC2848976
    6. karim2001khoury 19 Feb 2026
      We explored the spectrum of affected genes by hybridization to NimbleGen whole genome gene expression arrays, comparing untreated to PLX4032 treated (8 and 24 h) YUDOSO-BRAFWT melanoma cells. The results showed strong up

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the response of melanoma cells to the therapy PLX4032, indicating that the BRAFV600E variant is associated with a lack of activation of certain proteins in response to treatment, which suggests a predictive relationship regarding therapy response. Oncogenic: The mention of BRAFV600E in the context of melanoma cells implies its role as a somatic variant contributing to tumor development or progression, as it is a well-known oncogenic mutation in melanoma.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976 Predictive Oncogenic
    7. karim2001khoury 19 Feb 2026
      Real time RT-PCR demonstrated that known early response genes, FOS and JUNB, were activated within 30 min in YUDOSO-BRAFWT melanoma cells in response to PLX4032, an effect that was persistent for up to 8 h, whereas FOS w

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the response of BRAFV600E cells to PLX4032, indicating a correlation with treatment response. Oncogenic: The mention of BRAFV600E in the context of downregulation of FOS and the activation of ERK1/2 suggests that this somatic variant contributes to tumor behavior and progression.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976 Predictive Oncogenic
    8. karim2001khoury 19 Feb 2026
      We further explored the activation of downstream ERK targets and changes in gene expression that may shed more light on PLX4032 cellular responses and may provide markers to monitor therapy. Western blotting with phospho

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the cellular responses to PLX4032 therapy and mentions the activation of downstream ERK targets in relation to the BRAFV600E variant, indicating a correlation with treatment response. Oncogenic: The BRAFV600E variant is implicated in the inhibition of p90RSK activation in melanoma cells, suggesting its role in tumor development or progression.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976 Predictive Oncogenic
    9. karim2001khoury 19 Feb 2026
      We considered several known pathways by which PLX4032 could activate RAF1. We ruled out triggering an escape pathway, such as a receptor tyrosine kinase, by two independent approaches. First, traditional Western blotting

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the R89L variant of RAF1 alters its ability to bind Ras-GTP and its activation in response to PLX4032, indicating a change in molecular function. Oncogenic: The R89L variant is described in the context of its activation and role in signaling pathways, suggesting its contribution to tumor development or progression.

      Gene→Variant (gene-first): 3726:R89L

      Genes: 3726

      Variants: R89L

      CIViC paragraph-level PMC2848976 Functional Oncogenic
    10. karim2001khoury 19 Feb 2026
      Similar studies with RAF1 showed non-detectable activity in YULAC-BRAFV600E and YUMAC-BRAFV600K cells (data not shown). In contrast, a wide range of RAF1 kinase activity was observed in four independent BRAFWT melanoma c

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the activity of RAF1 kinase in relation to BRAFV600E and BRAFV600K variants, indicating that these variants alter the molecular function of RAF1, as evidenced by the observed kinase activity levels. Oncogenic: The mention of BRAFV600E and BRAFV600K in the context of non-detectable activity and their relationship to RAF1 activity suggests that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

      Genes: 673

      Variants: BRAFV600E BRAFV600K

      CIViC paragraph-level PMC2848976 Functional Oncogenic
    11. karim2001khoury 19 Feb 2026
      We therefore assessed BRAF and RAF1 enzymatic activity. Immune-complexes kinase assays showed, as expected, high BRAF activity in YULAC-BRAFV600E and YUMAC-BRAFV600K cells that was suppressed after treatment with PLX4032

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses the enzymatic activity of BRAF variants (BRAFV600E and BRAFV600K) and how their activity is altered by treatment with PLX4032, indicating a change in molecular function. Predictive: The mention of treatment with PLX4032 and its effect on the activity of BRAF variants suggests a correlation with response to therapy, indicating predictive evidence.

      Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

      Genes: 673

      Variants: BRAFV600E BRAFV600K

      CIViC paragraph-level PMC2848976 Functional Predictive
    12. karim2001khoury 19 Feb 2026
      Other intracellular signaling pathways were not, or slightly affected by PLX4032. We did not detect engagement of the AKT pathway (Figure S2A, pS6K and pAKT). There were only slight changes in the activated form of p38MA

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 8

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976
    13. karim2001khoury 19 Feb 2026
      The opposite effects of PLX4032 on ERK1/2 phosphorylation in YULAC-BRAFV600E and YUDOSO-BRAFWT melanoma cells were concentration dependent. Both cell types responded to the drug at 1 and 0.5 muM, but not at 0.1 muM (Figu

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the response of melanoma cells with the BRAFV600E variant to the drug PLX4032, indicating a correlation with treatment sensitivity. Oncogenic: The BRAFV600E variant is implicated in the context of melanoma cells, suggesting its role in tumor development or progression.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976 Predictive Oncogenic
    14. karim2001khoury 19 Feb 2026
      Changes in dephosphorylation and hyperphosphorylation of ERK1/2 in YULAC-BRAFV600E and YUDOSO-BRAFWT melanoma cells, respectively, occurred within 5 min, and progressed with similar kinetics (Figure 2B, pERK). The Wester

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses changes in the phosphorylation state of ERK1/2 in response to treatment, indicating that the BRAFV600E variant alters the molecular function of these proteins in melanoma cells. Oncogenic: The mention of the BRAFV600E variant in the context of melanoma cells suggests that it contributes to tumor development or progression, as it is associated with changes in signaling pathways relevant to cancer.

      Gene→Variant (gene-first): 673:BRAFV600E

      Genes: 673

      Variants: BRAFV600E

      CIViC paragraph-level PMC2848976 Functional Oncogenic
    15. karim2001khoury 19 Feb 2026
      The effects of PLX4032 on downstream RAF effectors were examined to further understand the mechanism of drug resistance. Unless otherwise stated, we used 1 muM of PLX4032, about 10x the IC50 of sensitive melanoma cells,

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effects of PLX4032 on BRAFV600E/K melanoma cells, indicating a correlation between the variant and response to the therapy, specifically in terms of ERK1/2 phosphorylation. Oncogenic: The mention of BRAFV600E/K in the context of melanoma cells suggests that these somatic variants contribute to tumor development or progression, as they are associated with the activation of the RAF-MEK-ERK pathway in cancer.

      Gene→Variant (gene-first): 673:BRAFV600K 673:V600E/K

      Genes: 673

      Variants: BRAFV600K V600E/K

      CIViC paragraph-level PMC2848976 Predictive Oncogenic
    16. karim2001khoury 19 Feb 2026
      The effect of PLX4032 was tested on melanoma cells isolated from primary and metastatic lesions in which BRAF, NRAS and PTEN mutations were characterized (Table 1). Dose response analyses showed that all the BRAF mutant

      [Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the sensitivity of BRAF mutant melanoma cell strains, including those with the V600E mutation, to the drug PLX4032, indicating a correlation between the variant and response to therapy. Oncogenic: The V600E variant is mentioned in the context of BRAF mutations in melanoma cells, suggesting its role in tumor development or progression as part of the BRAF mutation profile.

      Gene→Variant (gene-first): 673:V600E

      Genes: 673

      Variants: V600E

      CIViC paragraph-level PMC2848976 Predictive Oncogenic
    Visit annotations in context

    Tags

    Annotators

    URL

    pmc.ncbi.nlm.nih.gov/articles/PMC2848976/pdf/pcr0023-0190.pdf