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  2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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    1. karim2001khoury 19 Feb 2026
      Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers

      [Paper-level Aggregated] PMCID: PMC10618648

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The ERBB2 mutations V777L and G778A were identified in the tyrosine kinase domain, indicating their potential role in tumorigenesis. Functional: The T733I mutation was noted to be weakly transforming and associated with resistance to lapatinib, suggesting a functional impact on the behavior of the cancer cells.

      Gene→Variant (gene-first): ERBB2(2064):G778A ERBB2(2064):V777L ERBB2(2064):T733I

      Genes: ERBB2(2064)

      Variants: G778A V777L T733I

      CIViC paper-level aggregated PMC10618648
    2. karim2001khoury 19 Feb 2026
      We next selected two gastroesophageal PDX models with HER2 overexpression (IHC 3+) and ERBB2 amplification. We tested PDX.003.230, a model that is HER2 3+ and ERBB2 amplified. This model was also noted to have an ERBB2 T

      [Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The T733I mutation is associated with resistance to lapatinib and sensitivity to adavosertib, indicating its role in predicting treatment response. Oncogenic: The T733I mutation is described as weakly transforming, suggesting it contributes to tumor development or progression in the context of the PDX model.

      Gene→Variant (gene-first): 2064:T733I

      Genes: 2064

      Variants: T733I

      CIViC paragraph-level PMC10618648 Predictive Oncogenic
    3. karim2001khoury 19 Feb 2026
      We first assessed the combination of T-DXd with adavosertib in PDXs with low HER2 expression. PDX.003.204 (HER2 2+ IHC, CCNE1 amplified) demonstrated modest tumor growth inhibition with T-DXd monotherapy as shown by a re

      [Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage indicates that ERBB2 mutations (V777L, G778A) were identified in the tyrosine kinase domain, suggesting that these somatic variants contribute to tumor development or progression. Functional: The mention of ERBB2 mutations in the tyrosine kinase domain implies that these variants may alter molecular or biochemical function, which is characteristic of functional evidence.

      Gene→Variant (gene-first): 2064:G778A 2064:V777L

      Genes: 2064

      Variants: G778A V777L

      CIViC paragraph-level PMC10618648 Oncogenic Functional
    4. karim2001khoury 19 Feb 2026
      Apoptosis was assessed by annexin V staining to determine the effects of adavosertib in combination with DXd or T-DXd in MKN7 cells. Although both DXd and T-DXd were capable of inducing apoptosis (5-20%), combination of

      [Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 11

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 2064:E in 72

      Genes: 2064

      Variants: E in 72

      CIViC paragraph-level PMC10618648
    5. karim2001khoury 19 Feb 2026
      We next selected two gastroesophageal PDX models with HER2 overexpression (IHC 3+) and ERBB2 amplification. We tested PDX.003.230, a model that is HER2 3+ and ERBB2 amplified. This model was also noted to have an ERBB2 T

      [Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The T733I mutation is associated with resistance to lapatinib and sensitivity to adavosertib, indicating its role in predicting treatment response. Oncogenic: The T733I mutation is described as weakly transforming, suggesting it contributes to tumor development or progression in the context of the PDX model.

      Gene→Variant (gene-first): 2064:T733I

      Genes: 2064

      Variants: T733I

      CIViC paragraph-level PMC10618648 Predictive Oncogenic
    6. karim2001khoury 19 Feb 2026
      We first assessed the combination of T-DXd with adavosertib in PDXs with low HER2 expression. PDX.003.204 (HER2 2+ IHC, CCNE1 amplified) demonstrated modest tumor growth inhibition with T-DXd monotherapy as shown by a re

      [Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage indicates that ERBB2 mutations (V777L, G778A) were identified in the tyrosine kinase domain, suggesting that these somatic variants contribute to tumor development or progression. Functional: The mention of ERBB2 mutations in the tyrosine kinase domain implies that these variants may alter molecular or biochemical function, which is characteristic of functional evidence.

      Gene→Variant (gene-first): 2064:G778A 2064:V777L

      Genes: 2064

      Variants: G778A V777L

      CIViC paragraph-level PMC10618648 Oncogenic Functional
    7. karim2001khoury 19 Feb 2026
      Apoptosis was assessed by annexin V staining to determine the effects of adavosertib in combination with DXd or T-DXd in MKN7 cells. Although both DXd and T-DXd were capable of inducing apoptosis (5-20%), combination of

      [Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 11

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 2064:E in 72

      Genes: 2064

      Variants: E in 72

      CIViC paragraph-level PMC10618648
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    pmc.ncbi.nlm.nih.gov/articles/PMC10618648/pdf/4385.pdf