[Paper-level Aggregated] PMCID: PMC5762309

Evidence Type(s): Functional

Summary: Mutation: V559D | Summary: The V559D mutation alters the molecular function of the KIT protein, affecting cell proliferation, auto-phosphorylation, and phosphorylation at specific sites. It demonstrates changes in molecular function related to treatment response and is evidenced by its selectivity and efficacy in biochemical assays and signaling pathways.

Evidence Type: Functional Mutation: L576P | Summary: The L576P mutation alters molecular or biochemical function, as indicated by its mention in binding assays.

Evidence Type: Functional Mutation: A829P | Summary: The A829P mutation alters molecular or biochemical function, as suggested by its discussion in binding assays.

Evidence Type: Functional

Gene→Variant (gene-first): KIT(3815):V559D KIT(3815):L576P KIT(3815):A829P

Genes: KIT(3815)

Variants: V559D L576P A829P

[Paper-level Aggregated] PMCID: PMC5762309

Evidence Type(s): Oncogenic

Summary: Mutation: V559D | Summary: The V559D mutation is associated with tumor development and progression, as it contributes to tumor growth and is identified as a primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs). It is linked to the proliferation of BaF3-TEL-KIT-V559D cells and shows strong binding to the inhibitor CHMFL-KIT-031, indicating its role in tumor development.

Evidence Type: Oncogenic Mutation: L576P | Summary: The L576P mutation is mentioned as a primary mutant in the context of selective inhibition, indicating its role in tumor progression.

Evidence Type: Oncogenic Mutation: T670I | Summary: The T670I mutation is classified as a secondary mutant, contributing to tumor development in the context of selective inhibition.

Evidence Type: Oncogenic Mutation: V654A | Summary: The V654A mutation is noted as a secondary mutant involved in tumor progression, as indicated by its context in selective inhibition.

Evidence Type: Oncogenic Mutation: N822K | Summary: The N822K mutation is mentioned in the context of activation loop mutations, suggesting its contribution to tumor development.

Evidence Type: Oncogenic Mutation: D816V | Summary: The D816V mutation is described as an activation loop mutation, indicating its role in tumor progression.

Gene→Variant (gene-first): KIT(3815):V559D KIT(3815):L576P KIT(3815):T670I KIT(3815):V654A KIT(3815):N822K KIT(3815):D816V

Genes: KIT(3815)

Variants: V559D L576P T670I V654A N822K D816V

[Paper-level Aggregated] PMCID: PMC5762309

Evidence Type(s): Predictive

Summary: Mutation: V559D | Summary: The V559D mutation correlates with sensitivity to the KIT kinase inhibitor CHMFL-KIT-031, indicating a predictive relationship for treatment response. It is selectively inhibited by CHMFL-KIT-031, demonstrating its potential predictive value for therapy effectiveness. The mutation is associated with a dose-dependent inhibition of tumor growth, suggesting a correlation with treatment response.

Evidence Type: Predictive Mutation: L576P | Summary: The L576P mutation shows sensitivity to Imatinib, suggesting it may predict treatment response in patients with this variant.

Evidence Type: Predictive Mutation: V654A | Summary: The V654A mutation exhibits moderate sensitivity to CHMFL-KIT-031, indicating a predictive relationship for treatment response.

Evidence Type: Predictive Mutation: N822K | Summary: The N822K mutation shows similar sensitivity to Imatinib as V654A, suggesting it may predict treatment response.

Evidence Type: Predictive Mutation: D816V | Summary: The D816V mutation is resistant to both Imatinib and Sunitinib, indicating a predictive relationship for treatment resistance.

Evidence Type: Predictive Mutation: T670I | Summary: The T670I mutation is resistant to both Imatinib and Sunitinib, indicating a predictive relationship for treatment resistance.

Gene→Variant (gene-first): KIT(3815):V559D KIT(3815):L576P KIT(3815):V654A KIT(3815):N822K KIT(3815):D816V KIT(3815):T670I

Genes: KIT(3815)

Variants: V559D L576P V654A N822K D816V T670I

[Paragraph-level] PMCID: PMC5762309 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: V559D | Summary: The KIT V559D mutation is identified as a primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs), contributing to tumor development. Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters molecular function, as evidenced by its selectivity and efficacy in biochemical assays and signaling pathways. Evidence Type: Oncogenic | Mutation: L576P | Summary: The L576P mutation is mentioned as a primary mutant in the context of selective inhibition, indicating its role in tumor progression. Evidence Type: Oncogenic | Mutation: T670I | Summary: The T670I mutation is classified as a secondary mutant, contributing to tumor development in the context of selective inhibition. Evidence Type: Oncogenic | Mutation: V654A | Summary: The V654A mutation is noted as a secondary mutant involved in tumor progression, as indicated by its context in selective inhibition. Evidence Type: Oncogenic | Mutation: N822K | Summary: The N822K mutation is mentioned in the context of activation loop mutations, suggesting its contribution to tumor development. Evidence Type: Oncogenic | Mutation: D816V | Summary: The D816V mutation is described as an activation loop mutation, indicating its role in tumor progression.

Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: V559D | Summary: The V559D mutation is associated with a response to the CHMFL-KIT-031 treatment, which shows a dose-dependent inhibition of tumor growth, indicating its predictive value for therapy response. Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation contributes to tumor development or progression, as evidenced by its presence in a mouse model where tumor growth is being studied.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Predictive

Summary: Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation is associated with tumor growth, indicating its role in tumor development or progression. Evidence Type: Predictive | Mutation: V559D | Summary: The passage suggests that CHMFL-KIT-031 inhibits tumor growth in a model with the V559D mutation, indicating a potential correlation with treatment response.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: V559D | Summary: The variant KIT V559D is associated with a specific response to the inhibitor CHMFL-KIT-031, demonstrating its potential predictive value for therapy effectiveness. Evidence Type: Functional | Mutation: V559D | Summary: The KIT V559D variant alters the molecular function of the kinase, as evidenced by its impact on auto-phosphorylation and downstream signaling pathways in response to treatment.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: V559D | Summary: The KIT V559D mutant is selectively inhibited by CHMFL-KIT-031, indicating a correlation with response to this specific therapy. Evidence Type: Oncogenic | Mutation: V559D | Summary: The presence of the KIT V559D mutation suggests a role in tumor development or progression, as it is a specific mutant form of the KIT gene.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation is associated with strong binding to the inhibitor CHMFL-KIT-031, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: L576P | Summary: The L576P mutation is mentioned in the context of binding assays, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: A829P | Summary: The A829P mutation is also discussed in relation to binding assays, suggesting it alters molecular or biochemical function.

Gene→Variant (gene-first): 3815:A829P 3815:L576P 3815:V559D

Genes: 3815

Variants: A829P L576P V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters the phosphorylation of KIT at specific sites, indicating a change in molecular function related to the mutant's response to treatment. Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation contributes to tumor development or progression as it is associated with the anti-proliferative effects observed in transformed BaF3 cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters the molecular function of the KIT protein, as indicated by its role in auto-phosphorylation in the context of the study.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive

Summary: Evidence Type: Predictive | Mutation: V559D | Summary: The V559D mutation correlates with sensitivity to the KIT kinase inhibitor CHMFL-KIT-031, indicating a predictive relationship for treatment response. Evidence Type: Predictive | Mutation: L576P | Summary: The L576P mutation shows sensitivity to Imatinib, suggesting it may predict treatment response in patients with this variant. Evidence Type: Predictive | Mutation: V654A | Summary: The V654A mutation exhibits moderate sensitivity to CHMFL-KIT-031, indicating a predictive relationship for treatment response. Evidence Type: Predictive | Mutation: N822K | Summary: The N822K mutation shows similar sensitivity to Imatinib as V654A, suggesting it may predict treatment response. Evidence Type: Predictive | Mutation: D816V | Summary: The D816V mutation is resistant to both Imatinib and Sunitinib, indicating a predictive relationship for treatment resistance. Evidence Type: Predictive | Mutation: T670I | Summary: The T670I mutation is resistant to both Imatinib and Sunitinib, indicating a predictive relationship for treatment resistance.

Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters the molecular function of the KIT protein, as indicated by the selective inhibition of cell proliferation in BaF3-TEL-KIT-V559D cells. Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation contributes to tumor development or progression, as it is associated with the proliferation of BaF3-TEL-KIT-V559D cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paper-level Aggregated] PMCID: PMC5762309

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The KIT V559D mutation is described as the most prevalent primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs), indicating its role in tumorigenesis. Functional: The study demonstrates that CHMFL-KIT-031 selectively inhibits the proliferation and auto-phosphorylation of cells expressing the KIT V559D mutation, confirming its functional impact on mutant KIT signaling pathways. Predictive: The selectivity of CHMFL-KIT-031 for the KIT V559D mutation over other mutations and wild-type KIT suggests its potential as a predictive biomarker for treatment response in patients with GISTs harboring this specific mutation.

Gene→Variant (gene-first): KIT(3815):A829P KIT(3815):L576P KIT(3815):V559D KIT(3815):D816V KIT(3815):N822K KIT(3815):T670I KIT(3815):V654A

Genes: KIT(3815)

Variants: A829P L576P V559D D816V N822K T670I V654A

[Paragraph-level] PMCID: PMC5762309 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the selective inhibitor CHMFL-KIT-031 and its efficacy against the KIT V559D mutation, indicating a correlation with response to therapy. Oncogenic: The KIT V559D mutation is described as a primary gain-of-function mutation in GISTs, suggesting it contributes to tumor development or progression.

Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the tumor to the treatment with CHMFL-KIT-031, indicating a correlation between the V559D variant and the sensitivity to this specific therapy, as evidenced by tumor growth inhibition. Oncogenic: The V559D variant is implicated in tumor progression, as the passage describes its role in a mouse model where the variant is present and the tumor's response to treatment is evaluated.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant V559D is discussed in the context of tumor growth inhibition, indicating that it contributes to tumor development or progression in the specified cell model. Predictive: The mention of CHMFL-KIT-031 inhibiting tumor growth suggests a correlation between the V559D variant and response to this specific therapy.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the inhibitory effect of CHMFL-KIT-031 against the KIT V559D mutant, indicating a correlation with response to therapy, as evidenced by the IC50 values and selectivity over the wild-type KIT. Functional: The variant KIT V559D is shown to alter the molecular function by affecting the phosphorylation of specific sites and downstream mediators, demonstrating its role in biochemical activity as tested in various assays.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the KIT V559D mutant, suggesting a correlation with response to therapy. Oncogenic: The mention of the KIT V559D mutant in the context of selective inhibition implies that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the binding and selectivity of CHMFL-KIT-031 to the V559D, L576P, and A829P variants, indicating their potential response to therapy, particularly in the context of inhibitor selectivity. Functional: The results indicate that the variants (V559D, L576P, A829P) alter the binding characteristics of the compound CHMFL-KIT-031, suggesting a change in molecular function related to kinase activity.

Gene→Variant (gene-first): 3815:A829P 3815:L576P 3815:V559D

Genes: 3815

Variants: A829P L576P V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the KIT V559D mutant affects phosphorylation at specific sites, indicating that the variant alters molecular function related to protein activity. Oncogenic: The context of the passage suggests that the KIT V559D variant contributes to tumor development or progression, as it is involved in the anti-proliferation assay of transformed cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the variant V559D alters the molecular function of the KIT protein by affecting its auto-phosphorylation activity in specific cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of various KIT variants, including V559D, L576P, and others, to different therapies such as CHMFL-KIT-031 and Imatinib, indicating their correlation with treatment sensitivity and resistance. Oncogenic: The variants mentioned, particularly V559D and L576P, are described in the context of their role in transforming BaF3 cells, suggesting that they contribute to tumor development or progression.

Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the proliferation of cells with the V559D variant, suggesting a correlation with response to this specific therapy. Oncogenic: The mention of the V559D variant in the context of inhibiting cell proliferation implies that it contributes to tumor development or progression, as it is associated with a specific cell line used in cancer research.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the selective inhibitor CHMFL-KIT-031 and its efficacy against the KIT V559D mutation, indicating a correlation with response to therapy. Oncogenic: The KIT V559D mutation is described as a primary gain-of-function mutation in GISTs, suggesting it contributes to tumor development or progression.

Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the tumor to the treatment with CHMFL-KIT-031, indicating a correlation between the V559D variant and the sensitivity to this specific therapy, as evidenced by tumor growth inhibition. Oncogenic: The V559D variant is implicated in tumor progression, as the passage describes its role in a mouse model where the variant is present and the tumor's response to treatment is evaluated.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant V559D is discussed in the context of tumor growth inhibition, indicating that it contributes to tumor development or progression in the specified cell model. Predictive: The mention of CHMFL-KIT-031 inhibiting tumor growth suggests a correlation between the V559D variant and response to this specific therapy.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the inhibitory effect of CHMFL-KIT-031 against the KIT V559D mutant, indicating a correlation with response to therapy, as evidenced by the IC50 values and selectivity over the wild-type KIT. Functional: The variant KIT V559D is shown to alter the molecular function by affecting the phosphorylation of specific sites and downstream mediators, demonstrating its role in biochemical activity as tested in various assays.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the KIT V559D mutant, suggesting a correlation with response to therapy. Oncogenic: The mention of the KIT V559D mutant in the context of selective inhibition implies that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the binding and selectivity of CHMFL-KIT-031 to the V559D, L576P, and A829P variants, indicating their potential response to therapy, particularly in the context of inhibitor selectivity. Functional: The results indicate that the variants (V559D, L576P, A829P) alter the binding characteristics of the compound CHMFL-KIT-031, suggesting a change in molecular function related to kinase activity.

Gene→Variant (gene-first): 3815:A829P 3815:L576P 3815:V559D

Genes: 3815

Variants: A829P L576P V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the KIT V559D mutant affects phosphorylation at specific sites, indicating that the variant alters molecular function related to protein activity. Oncogenic: The context of the passage suggests that the KIT V559D variant contributes to tumor development or progression, as it is involved in the anti-proliferation assay of transformed cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the variant V559D alters the molecular function of the KIT protein by affecting its auto-phosphorylation activity in specific cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of various KIT variants, including V559D, L576P, and others, to different therapies such as CHMFL-KIT-031 and Imatinib, indicating their correlation with treatment sensitivity and resistance. Oncogenic: The variants mentioned, particularly V559D and L576P, are described in the context of their role in transforming BaF3 cells, suggesting that they contribute to tumor development or progression.

Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the proliferation of cells with the V559D variant, suggesting a correlation with response to this specific therapy. Oncogenic: The mention of the V559D variant in the context of inhibiting cell proliferation implies that it contributes to tumor development or progression, as it is associated with a specific cell line used in cancer research.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D