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    1. karim2001khoury 19 Feb 2026
      Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity

      [Paper-level Aggregated] PMCID: PMC11551396

      Evidence Type(s): Oncogenic, Predictive, Functional

      Justification: Oncogenic: The text indicates that the exon 20 insertion variants (insASV and insSVD) exhibit enhanced catalytic rates and lower Km values compared to WT EGFR, suggesting their role in promoting cancer through increased activity. Predictive: The study evaluates the sensitivity of various EGFR mutations, including L858R and exon 20 insertions, to different inhibitors, indicating that the presence of specific mutations can predict the effectiveness of targeted therapies. Functional: The biochemical analysis of the variants, including kinetic studies and enzyme assays, demonstrates their functional characteristics, such as catalytic efficiency and inhibitor sensitivity, which are critical for understanding their role in cancer biology.

      Gene→Variant (gene-first): EGFR(1956):C797 EGFR(1956):T790 EGFR(1956):T790M EGFR(1956):V948R TXK(7294):Glu4 EGFR(1956):L858R EGFR(1956):N771insSVD

      Genes: EGFR(1956) TXK(7294)

      Variants: C797 T790 T790M V948R Glu4 L858R N771insSVD

      CIViC paper-level aggregated PMC11551396
    2. karim2001khoury 19 Feb 2026
      In the TAS6417 structure, the tricyclic core of the inhibitor forms dual hydrogen bonds to the kinase hinge, and the acrylamide forms the expected covalent bond with C797 (Fig. 4F). The quinoline substituent extends into

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variant C797 interacts with the inhibitor at a molecular level, specifically forming covalent bonds and influencing the binding interactions within the kinase structure.

      Gene→Variant (gene-first): 1956:C797 1956:T790

      Genes: 1956

      Variants: C797 T790

      CIViC paragraph-level PMC11551396 Functional
    3. karim2001khoury 19 Feb 2026
      The core of TAK-788, which is identical to osimertinib, binds in essentially the same manner as osimertinib and the additional isopropyl ester of TAK-788 extends into the back pocket alongside the gatekeeper T790 and sim

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.

      Gene→Variant (gene-first): 1956:T790

      Genes: 1956

      Variants: T790

      CIViC paragraph-level PMC11551396 Functional Predictive
    4. karim2001khoury 19 Feb 2026
      Poziotinib is an anilinoquinazoline inhibitor and binds in the manner expected for this compound class, with a single hydrogen bond to the hinge region, and the halogen-substituted aniline group in the back pocket adjace

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the C797 variant forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Oncogenic: The T790M and V948R variants are described in the context of adopting an inactive kinase conformation, which suggests their role in tumor progression or development.

      Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R

      Genes: 1956

      Variants: C797 T790M V948R

      CIViC paragraph-level PMC11551396 Functional Oncogenic
    5. karim2001khoury 19 Feb 2026
      BAY-33 binds with its pyridine group adjacent to the hinge region of the kinase, where it forms a single hydrogen bond with the backbone amide of M793 (Fig. 4 A and B). The fluoro- and methoxy- substituted anilino group

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 15

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 1956:T790

      Genes: 1956

      Variants: T790

      CIViC paragraph-level PMC11551396
    6. karim2001khoury 19 Feb 2026
      As we have been unable to obtain suitable crystals of the insASV or insSVD variants, we determined cocrystal structures of BAY-33, TAK-788, TAS6417, and poziotinib with WT EGFR to better understand their binding modes an

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 1956:T790M 1956:V948R

      Genes: 1956

      Variants: T790M V948R

      CIViC paragraph-level PMC11551396
    7. karim2001khoury 19 Feb 2026
      To better understand the degree of correlation in drug sensitivity across WT and various EGFR mutants, we plotted pairwise comparisons of IC50 values (Fig. 2). This analysis revealed little if any correlation in inhibito

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the correlation between the L858R variant and drug sensitivity, indicating that the L858R mutation has a drug-sensitizing effect, which aligns with predictive evidence regarding therapy response. Oncogenic: The L858R variant is implicated in greater potency against EGFR compared to WT EGFR, suggesting its role in tumor development or progression, which is characteristic of oncogenic evidence.

      Gene→Variant (gene-first): 1956:L858R

      Genes: 1956

      Variants: L858R

      CIViC paragraph-level PMC11551396 Predictive Oncogenic
    8. karim2001khoury 19 Feb 2026
      We measured the biochemical potencies of a diverse panel of EGFR inhibitors against insASV, insSVD, and insNPG exon 20 insertion mutants and for comparison against WT EGFR and the L858R and L858R/T790M point mutants. Inh

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.

      Gene→Variant (gene-first): 1956:L858R 1956:T790M

      Genes: 1956

      Variants: L858R T790M

      CIViC paragraph-level PMC11551396 Predictive Functional
    9. karim2001khoury 19 Feb 2026
      The enhanced inhibitor sensitivity of EGFR L858R and exon 19 deletions stems, at least in part, from their decreased affinity for ATP compared to the WT EGFR. While the Km, ATP values of insASV and insSVD are higher as c

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the enhanced inhibitor sensitivity of the L858R variant in relation to its decreased affinity for ATP, indicating a correlation with sensitivity to EGFR TKIs, which aligns with predictive evidence. Oncogenic: The passage implies that the L858R variant contributes to oncogenicity, as it discusses the variant's biochemical properties and their relation to tumor development and progression.

      Gene→Variant (gene-first): 1956:L858R

      Genes: 1956

      Variants: L858R

      CIViC paragraph-level PMC11551396 Predictive Oncogenic
    10. karim2001khoury 19 Feb 2026
      We used a coupled enzyme assay to determine enzyme kinetic parameters for these exon 20 insertions, as well as for WT, L858R, and L858R/T790M EGFR for comparison. This well-established continuous assay employs pyruvate k

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.

      Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M

      Genes: 7294 1956

      Variants: Glu4 L858R T790M

      CIViC paragraph-level PMC11551396 Functional
    11. karim2001khoury 19 Feb 2026
      Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely res

      [Paragraph-level] PMCID: PMC11551396 Section: ABSTRACT PassageIndex: 3

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the drug sensitivity and resistance of the exon 20 insertion variants, indicating their correlation with response to specific therapies, particularly EGFR tyrosine kinase inhibitors. Oncogenic: The passage describes somatic mutations in the EGFR gene, specifically the exon 20 insertion variants, which contribute to tumor development in non-small cell lung cancer.

      Gene→Variant (gene-first): 1956:L858R 1956:N771insSVD

      Genes: 1956

      Variants: L858R N771insSVD

      CIViC paragraph-level PMC11551396 Predictive Oncogenic
    12. karim2001khoury 19 Feb 2026
      In the TAS6417 structure, the tricyclic core of the inhibitor forms dual hydrogen bonds to the kinase hinge, and the acrylamide forms the expected covalent bond with C797 (Fig. 4F). The quinoline substituent extends into

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variant C797 interacts with the inhibitor at a molecular level, specifically forming covalent bonds and influencing the binding interactions within the kinase structure.

      Gene→Variant (gene-first): 1956:C797 1956:T790

      Genes: 1956

      Variants: C797 T790

      CIViC paragraph-level PMC11551396 Functional
    13. karim2001khoury 19 Feb 2026
      The core of TAK-788, which is identical to osimertinib, binds in essentially the same manner as osimertinib and the additional isopropyl ester of TAK-788 extends into the back pocket alongside the gatekeeper T790 and sim

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.

      Gene→Variant (gene-first): 1956:T790

      Genes: 1956

      Variants: T790

      CIViC paragraph-level PMC11551396 Functional Predictive
    14. karim2001khoury 19 Feb 2026
      Poziotinib is an anilinoquinazoline inhibitor and binds in the manner expected for this compound class, with a single hydrogen bond to the hinge region, and the halogen-substituted aniline group in the back pocket adjace

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the C797 variant forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Oncogenic: The T790M and V948R variants are described in the context of adopting an inactive kinase conformation, which suggests their role in tumor progression or development.

      Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R

      Genes: 1956

      Variants: C797 T790M V948R

      CIViC paragraph-level PMC11551396 Functional Oncogenic
    15. karim2001khoury 19 Feb 2026
      BAY-33 binds with its pyridine group adjacent to the hinge region of the kinase, where it forms a single hydrogen bond with the backbone amide of M793 (Fig. 4 A and B). The fluoro- and methoxy- substituted anilino group

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 15

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 1956:T790

      Genes: 1956

      Variants: T790

      CIViC paragraph-level PMC11551396
    16. karim2001khoury 19 Feb 2026
      As we have been unable to obtain suitable crystals of the insASV or insSVD variants, we determined cocrystal structures of BAY-33, TAK-788, TAS6417, and poziotinib with WT EGFR to better understand their binding modes an

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14

      Evidence Type(s): None

      Justification: Not enough information in this passage.

      Gene→Variant (gene-first): 1956:T790M 1956:V948R

      Genes: 1956

      Variants: T790M V948R

      CIViC paragraph-level PMC11551396
    17. karim2001khoury 19 Feb 2026
      To better understand the degree of correlation in drug sensitivity across WT and various EGFR mutants, we plotted pairwise comparisons of IC50 values (Fig. 2). This analysis revealed little if any correlation in inhibito

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the correlation between the L858R variant and drug sensitivity, indicating that the L858R mutation has a drug-sensitizing effect, which aligns with predictive evidence regarding therapy response. Oncogenic: The L858R variant is implicated in greater potency against EGFR compared to WT EGFR, suggesting its role in tumor development or progression, which is characteristic of oncogenic evidence.

      Gene→Variant (gene-first): 1956:L858R

      Genes: 1956

      Variants: L858R

      CIViC paragraph-level PMC11551396 Predictive Oncogenic
    18. karim2001khoury 19 Feb 2026
      We measured the biochemical potencies of a diverse panel of EGFR inhibitors against insASV, insSVD, and insNPG exon 20 insertion mutants and for comparison against WT EGFR and the L858R and L858R/T790M point mutants. Inh

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.

      Gene→Variant (gene-first): 1956:L858R 1956:T790M

      Genes: 1956

      Variants: L858R T790M

      CIViC paragraph-level PMC11551396 Predictive Functional
    19. karim2001khoury 19 Feb 2026
      The enhanced inhibitor sensitivity of EGFR L858R and exon 19 deletions stems, at least in part, from their decreased affinity for ATP compared to the WT EGFR. While the Km, ATP values of insASV and insSVD are higher as c

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the enhanced inhibitor sensitivity of the L858R variant in relation to its decreased affinity for ATP, indicating a correlation with sensitivity to EGFR TKIs, which aligns with predictive evidence. Oncogenic: The passage implies that the L858R variant contributes to oncogenicity, as it discusses the variant's biochemical properties and their relation to tumor development and progression.

      Gene→Variant (gene-first): 1956:L858R

      Genes: 1956

      Variants: L858R

      CIViC paragraph-level PMC11551396 Predictive Oncogenic
    20. karim2001khoury 19 Feb 2026
      We used a coupled enzyme assay to determine enzyme kinetic parameters for these exon 20 insertions, as well as for WT, L858R, and L858R/T790M EGFR for comparison. This well-established continuous assay employs pyruvate k

      [Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.

      Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M

      Genes: 7294 1956

      Variants: Glu4 L858R T790M

      CIViC paragraph-level PMC11551396 Functional
    21. karim2001khoury 19 Feb 2026
      Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely res

      [Paragraph-level] PMCID: PMC11551396 Section: ABSTRACT PassageIndex: 3

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the drug sensitivity and resistance of the exon 20 insertion variants, indicating their correlation with response to specific therapies, particularly EGFR tyrosine kinase inhibitors. Oncogenic: The passage describes somatic mutations in the EGFR gene, specifically the exon 20 insertion variants, which contribute to tumor development in non-small cell lung cancer.

      Gene→Variant (gene-first): 1956:L858R 1956:N771insSVD

      Genes: 1956

      Variants: L858R N771insSVD

      CIViC paragraph-level PMC11551396 Predictive Oncogenic
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    pmc.ncbi.nlm.nih.gov/articles/PMC11551396/pdf/pnas.202417144.pdf