[Paper-level Aggregated] PMCID: PMC9398166

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Justification: Oncogenic: The text discusses various ALK mutations, including G1202R and L1196M, which are described as major resistance mechanisms to ALK inhibitors, indicating their role in oncogenesis. Functional: The evidence describes the biochemical characterization of TPX-0131's potency against various ALK mutations, demonstrating its functional ability to inhibit both wild-type and mutant ALK, including resistance mutations. Predictive: The text indicates that TPX-0131 was designed to avoid resistance mutations and shows significant potency against them, suggesting its potential predictive value for treatment outcomes in patients with these mutations. Prognostic: The discussion of TPX-0131's efficacy against a range of ALK mutations, including those associated with resistance, implies that the presence of these mutations could influence treatment response and patient prognosis.

Gene→Variant (gene-first): ALK(238):C1156Y ALK(238):D1203N ALK(238):E1210K ALK(238):F1174C ALK(238):F1174L ALK(238):F1174S ALK(238):F1245C ALK(238):G1202 ALK(238):G1202R ALK(238):G1269A ALK(238):G1269S ALK(238):I1171N ALK(238):L1152P ALK(238):L1152R ALK(238):L1196M ALK(238):L1198F ALK(238):R1275Q ALK(238):S1206C ALK(238):S1206R ALK(238):T1151-L1152 insT ALK(238):T1151M ALK(238):V1180L ALK(238):I1171N/S ALK(238):L1204V ALK(238):S/T ALK(238):L1198

Genes: ALK(238)

Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L I1171N/S L1204V S/T L1198

[Paragraph-level] PMCID: PMC9398166 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the G1202R and L1196M mutations are major resistance mechanisms to ALK inhibitors, indicating that these variants correlate with resistance to specific therapies. Oncogenic: The G1202R and L1196M mutations are described as resistance mechanisms that contribute to tumor progression, particularly in the context of ALK inhibitors, suggesting their role in oncogenesis.

Gene→Variant (gene-first): 238:G1202R 238:L1196M

Genes: 238

Variants: G1202R L1196M

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation of TPX-0131 treatment with tumor growth inhibition and suppression of ALK phosphorylation, indicating that the G1202R, L1196M, and L1198F variants are associated with resistance to therapy and response to treatment. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of ALK resistance mutations, suggesting their role in tumor development or progression as they are associated with the EML4-ALK fusion in a cancer model.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of tumor models harboring specific ALK mutations (G1202R, L1196M, L1198F) to the therapy TPX-0131, indicating a correlation between the variants and treatment efficacy. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of tumor models, suggesting that they contribute to tumor development or progression as part of the EML4-ALK fusion.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the variants G1202R, L1196M, and L1198F correlate with the response to the ALK inhibitor TPX-0131, indicating their role in resistance to therapy. Oncogenic: The variants mentioned are part of ALK oncogenic fusion proteins, which are implicated in tumor development and progression, as evidenced by their evaluation in assays measuring ALK autophosphorylation.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198 L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the ALK G1202R/G1269A/L1204V triple mutation to the TPX-0131 inhibitor, indicating a correlation with treatment sensitivity. Oncogenic: The mention of the EML4-ALK compound mutations, including G1202R, G1269A, and L1204V, in the context of cell proliferation assays suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 238:G1202R 238:G1269A 238:L1204V

Genes: 238

Variants: G1202R G1269A L1204V

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating that the variant mutations correlate with the response to the therapy, specifically highlighting the differences in inhibition potency against different mutations. Oncogenic: The passage describes the use of engineered Ba/F3 cells expressing oncogenic EML4-ALK variants, indicating that these mutations contribute to tumor development or progression, as they are associated with resistance to ALK inhibitors.

Gene→Variant (gene-first): 238:C1156Y 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:I1171N/S 238:L1196M 238:L1198F 238:L1204V 238:S/T

Genes: 238

Variants: C1156Y G1202R G1269A G1269S I1171N I1171N/S L1196M L1198F L1204V S/T

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating its effectiveness as a therapy for these specific variants, which correlates with treatment response. Functional: The passage describes the biochemical characterization of TPX-0131's inhibition of ALK mutations, focusing on its molecular properties and binding interactions that alter the function of the ALK protein.

Gene→Variant (gene-first): 238:C1156Y 238:D1203N 238:E1210K 238:F1174C 238:F1174L 238:F1174S 238:F1245C 238:G1202 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:L1152P 238:L1152R 238:L1196M 238:L1198F 238:R1275Q 238:S1206C 238:S1206R 238:T1151-L1152 insT 238:T1151M 238:V1180L

Genes: 238

Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses resistance mutations, including G1202, in the context of second-generation ALK inhibitors and their reduced potency, indicating a correlation with treatment response. Oncogenic: The mention of G1202 as a resistance mutation suggests that it contributes to tumor development or progression by obstructing binding and reducing the efficacy of ALK inhibitors.

Gene→Variant (gene-first): 238:G1202

Genes: 238

Variants: G1202

[Paragraph-level] PMCID: PMC9398166 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the G1202R and L1196M mutations are major resistance mechanisms to ALK inhibitors, indicating that these variants correlate with resistance to specific therapies. Oncogenic: The G1202R and L1196M mutations are described as resistance mechanisms that contribute to tumor progression, particularly in the context of ALK inhibitors, suggesting their role in oncogenesis.

Gene→Variant (gene-first): 238:G1202R 238:L1196M

Genes: 238

Variants: G1202R L1196M

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation of TPX-0131 treatment with tumor growth inhibition and suppression of ALK phosphorylation, indicating that the G1202R, L1196M, and L1198F variants are associated with resistance to therapy and response to treatment. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of ALK resistance mutations, suggesting their role in tumor development or progression as they are associated with the EML4-ALK fusion in a cancer model.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of tumor models harboring specific ALK mutations (G1202R, L1196M, L1198F) to the therapy TPX-0131, indicating a correlation between the variants and treatment efficacy. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of tumor models, suggesting that they contribute to tumor development or progression as part of the EML4-ALK fusion.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the variants G1202R, L1196M, and L1198F correlate with the response to the ALK inhibitor TPX-0131, indicating their role in resistance to therapy. Oncogenic: The variants mentioned are part of ALK oncogenic fusion proteins, which are implicated in tumor development and progression, as evidenced by their evaluation in assays measuring ALK autophosphorylation.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198 L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the ALK G1202R/G1269A/L1204V triple mutation to the TPX-0131 inhibitor, indicating a correlation with treatment sensitivity. Oncogenic: The mention of the EML4-ALK compound mutations, including G1202R, G1269A, and L1204V, in the context of cell proliferation assays suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 238:G1202R 238:G1269A 238:L1204V

Genes: 238

Variants: G1202R G1269A L1204V

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating that the variant mutations correlate with the response to the therapy, specifically highlighting the differences in inhibition potency against different mutations. Oncogenic: The passage describes the use of engineered Ba/F3 cells expressing oncogenic EML4-ALK variants, indicating that these mutations contribute to tumor development or progression, as they are associated with resistance to ALK inhibitors.

Gene→Variant (gene-first): 238:C1156Y 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:I1171N/S 238:L1196M 238:L1198F 238:L1204V 238:S/T

Genes: 238

Variants: C1156Y G1202R G1269A G1269S I1171N I1171N/S L1196M L1198F L1204V S/T

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating its effectiveness as a therapy for these specific variants, which correlates with treatment response. Functional: The passage describes the biochemical characterization of TPX-0131's inhibition of ALK mutations, focusing on its molecular properties and binding interactions that alter the function of the ALK protein.

Gene→Variant (gene-first): 238:C1156Y 238:D1203N 238:E1210K 238:F1174C 238:F1174L 238:F1174S 238:F1245C 238:G1202 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:L1152P 238:L1152R 238:L1196M 238:L1198F 238:R1275Q 238:S1206C 238:S1206R 238:T1151-L1152 insT 238:T1151M 238:V1180L

Genes: 238

Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses resistance mutations, including G1202, in the context of second-generation ALK inhibitors and their reduced potency, indicating a correlation with treatment response. Oncogenic: The mention of G1202 as a resistance mutation suggests that it contributes to tumor development or progression by obstructing binding and reducing the efficacy of ALK inhibitors.

Gene→Variant (gene-first): 238:G1202

Genes: 238

Variants: G1202