TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations
[Paper-level Aggregated] PMCID: PMC9398166
Evidence Type(s): Functional
Summary: Mutation: I1171N/S/T | Summary: The I1171N/S/T mutations are described in the context of their impact on the potency of TPX-0131, indicating that these mutations alter the molecular function related to drug response.
Gene→Variant (gene-first): NA:I1171N/S/T
Genes: NA
Variants: I1171N/S/T
TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations
[Paper-level Aggregated] PMCID: PMC9398166
Evidence Type(s): Oncogenic
Summary: Mutation: G1202 | Summary: The G1202 mutation contributes to tumor development by obstructing binding of ALK inhibitors, which is characteristic of oncogenic behavior in cancer progression.
Evidence Type: Oncogenic Mutation: G1202R | Summary: The G1202R mutation is part of the EML4-ALK oncogenic fusion proteins and is described as a major resistance mechanism to first-generation ALK inhibitors, contributing to tumor development and progression. It is also noted as a solvent front mutation that demonstrates potent inhibition of cell proliferation against cells harboring this mutation.
Evidence Type: Oncogenic Mutation: L1196M | Summary: The L1196M mutation is identified as a gatekeeper mutation and a significant resistance mechanism to first-generation ALK inhibitors, contributing to tumor development. It is included in the EML4-ALK oncogenic fusion context, indicating its role in tumor progression, with TPX-0131 showing significantly greater potency against this mutation compared to previous ALK inhibitors.
Evidence Type: Oncogenic Mutation: L1198F | Summary: The L1198F mutation is characterized as a hinge region mutation and is part of the EML4-ALK oncogenic fusion proteins, suggesting its role in tumor progression. TPX-0131 exhibits high potency against this mutation.
Evidence Type: Oncogenic Mutation: G1269A | Summary: The G1269A mutation is noted as a resistance mutation, with TPX-0131 showing moderate potency against cells harboring this mutation.
Gene→Variant (gene-first): ALK(238):G1202 ALK(238):G1202R ALK(238):L1196M ALK(238):L1198F ALK(238):G1269A
Genes: ALK(238)
Variants: G1202 G1202R L1196M L1198F G1269A
TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations
[Paper-level Aggregated] PMCID: PMC9398166
Evidence Type(s): Predictive
Summary: Mutation: G1202 | Summary: The G1202 mutation is associated with resistance to second-generation ALK inhibitors, indicating its relevance in predicting treatment response and resistance to specific therapies.
Evidence Type: Predictive Mutation: C1156Y | Summary: C1156Y is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy.
Evidence Type: Predictive Mutation: E1210K | Summary: E1210K is inhibited by TPX-0131 with an IC50 of <1 nmol/L, suggesting it correlates with response to this specific therapy.
Evidence Type: Predictive Mutation: S1206C | Summary: S1206C is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy.
Evidence Type: Predictive Mutation: L1198F | Summary: The L1198F mutation, in conjunction with G1202R, demonstrates resistance to lorlatinib, highlighting its predictive value for treatment response to TPX-0131. Additionally, the L1198F mutation in the EML4-ALK fusion shows a complete tumor regression in response to TPX-0131 treatment in a CDX model.
Evidence Type: Predictive Mutation: L1196M | Summary: The L1196M mutation, when combined with G1202R, shows a similar resistance pattern to lorlatinib, indicating its role in treatment response to TPX-0131. It is also part of the compound mutation G1202R/L1196M, which shows a correlation with response to TPX-0131 treatment, indicating its predictive value in therapy.
Evidence Type: Predictive Mutation: T1151M | Summary: T1151M is inhibited by TPX-0131 with an IC50 of 1 to 2 nmol/L, suggesting it correlates with response to this specific therapy.
Evidence Type: Predictive Mutation: F1174L | Summary: F1174L is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy.
Evidence Type: Predictive Mutation: F1245C | Summary: F1245C is inhibited by TPX-0131 with an IC50 of <1 nmol/L, suggesting it correlates with response to this specific therapy.
Evidence Type: Predictive Mutation: R1275Q | Summary: R1275Q is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy.
Evidence Type: Predictive Mutation: G1202R | Summary: The G1202R mutation is associated with a response to TPX-0131 treatment, demonstrating dose-dependent tumor growth inhibition (TGI) in a CDX model. It is also associated with resistance to lorlatinib, as indicated by the higher IC50 values, suggesting that it correlates with treatment response to TPX-0131. Additionally, the G1202R mutation in the EML4-ALK fusion is associated with a response to TPX-0131 treatment, as evidenced by the correlation of tumor growth inhibition with TPX-0131 exposure and suppression of ALK phosphorylation.
Evidence Type: Predictive Mutation: G1269A | Summary: The G1269A mutation is linked to the response to TPX-0131, suggesting it may predict sensitivity to this specific therapy.
Evidence Type: Predictive Mutation: L1204V | Summary: The L1204V mutation shows a correlation with the response to TPX-0131, indicating its predictive role in therapy effectiveness.
Gene→Variant (gene-first): ALK(238):G1202 ALK(238):C1156Y ALK(238):E1210K ALK(238):S1206C ALK(238):L1198F ALK(238):L1196M ALK(238):T1151M ALK(238):F1174L ALK(238):F1245C ALK(238):R1275Q ALK(238):G1202R ALK(238):G1269A ALK(238):L1204V
Genes: ALK(238)
Variants: G1202 C1156Y E1210K S1206C L1198F L1196M T1151M F1174L F1245C R1275Q G1202R G1269A L1204V
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung c
[Paragraph-level] PMCID: PMC9398166 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: G1202R | Summary: The G1202R mutation is described as a major resistance mechanism to first-generation ALK inhibitors and contributes to tumor development, as evidenced by its role in ALK compound mutation-dependent xenograft models. Evidence Type: Oncogenic | Mutation: L1196M | Summary: The L1196M mutation is identified as a significant resistance mechanism to first-generation ALK inhibitors, indicating its contribution to tumor development in the context of ALK mutations.
Gene→Variant (gene-first): 238:G1202R 238:L1196M
Genes: 238
Variants: G1202R L1196M
The correlation of inhibition of ALK phosphorylation (Tyr1282/1283) was evaluated as a function of TPX-0131 plasma exposure analysis using the Ba/F3 CDX model harboring the EML4-ALK fusion with the G1202R/L1196M compound
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive
Summary: Evidence Type: Predictive | Mutation: G1202R | Summary: The G1202R mutation is associated with a response to TPX-0131 treatment, as evidenced by the correlation of tumor growth inhibition with TPX-0131 exposure and suppression of ALK phosphorylation. Evidence Type: Predictive | Mutation: L1196M | Summary: The L1196M mutation is part of the compound mutation G1202R/L1196M, which shows a correlation with response to TPX-0131 treatment, indicating its predictive value in therapy. Evidence Type: Predictive | Mutation: L1198F | Summary: The L1198F mutation is included in the compound mutation G1202R/L1198F, which demonstrates a correlation with the efficacy of TPX-0131 treatment, supporting its predictive role in therapy.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198F
TGI and the pharmacodynamic modulation of ALK were performed in cell-derived xenograft (CDX) models for clinically relevant ALK mutants that limit the utility of previous generations of ALK inhibitors (e.g. SFM, compound
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive
Summary: Evidence Type: Predictive | Mutation: G1202R | Summary: The G1202R mutation in the EML4-ALK fusion is associated with a response to TPX-0131 treatment, demonstrating dose-dependent tumor growth inhibition (TGI) in a CDX model. Evidence Type: Predictive | Mutation: L1198F | Summary: The L1198F mutation in the EML4-ALK fusion, when combined with G1202R, shows a complete tumor regression in response to TPX-0131 treatment in a CDX model. Evidence Type: Predictive | Mutation: L1196M | Summary: The L1196M mutation in the EML4-ALK fusion, in combination with G1202R, is linked to dose-dependent efficacy of TPX-0131 treatment, resulting in complete tumor regression in a CDX model.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198F
To confirm the results obtained from the cell proliferation assays, TPX-0131 and select other ALK inhibitors were evaluated in assays measuring pharmacodynamic modulation of ALK (autophosphorylation). TPX-0131 suppressed
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Summary: Evidence Type: Predictive | Mutation: G1202R | Summary: The G1202R mutation is associated with resistance to lorlatinib, as indicated by the higher IC50 values, suggesting that it correlates with treatment response to TPX-0131. Evidence Type: Predictive | Mutation: L1196M | Summary: The L1196M mutation, when combined with G1202R, shows a similar resistance pattern to lorlatinib, indicating its role in treatment response to TPX-0131. Evidence Type: Predictive | Mutation: L1198F | Summary: The L1198F mutation, in conjunction with G1202R, demonstrates resistance to lorlatinib, highlighting its predictive value for treatment response to TPX-0131. Evidence Type: Oncogenic | Mutation: G1202R | Summary: The G1202R mutation is part of the EML4-ALK oncogenic fusion proteins, contributing to tumor development and progression. Evidence Type: Oncogenic | Mutation: L1196M | Summary: The L1196M mutation is included in the EML4-ALK oncogenic fusion context, indicating its contribution to tumor development. Evidence Type: Oncogenic | Mutation: L1198F | Summary: The L1198F mutation is also part of the EML4-ALK oncogenic fusion proteins, suggesting its role in tumor progression.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198 L1198F
In cell proliferation assays, TPX-0131 was the most potent inhibitor against a range of EML4-ALK compound mutations (Table 2). TPX-0131 inhibited six of nine compound mutations with IC50 < 1 nmol/L, had IC50 < 10 nmol/L
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive
Summary: Evidence Type: Predictive | Mutation: G1202R | Summary: The G1202R mutation is associated with a response to the TPX-0131 inhibitor, indicating its predictive value for therapy effectiveness. Evidence Type: Predictive | Mutation: G1269A | Summary: The G1269A mutation is linked to the response to TPX-0131, suggesting it may predict sensitivity to this specific therapy. Evidence Type: Predictive | Mutation: L1204V | Summary: The L1204V mutation shows a correlation with the response to TPX-0131, indicating its predictive role in therapy effectiveness.
Gene→Variant (gene-first): 238:G1202R 238:G1269A 238:L1204V
Genes: 238
Variants: G1202R G1269A L1204V
To enable comparisons of TPX-0131 with previous generations of ALK inhibitors, a panel of matched cell lines was created that are dependent on ALK resistance mutations found in patients as well as other mutations that ma
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Summary: Evidence Type: Oncogenic | Mutation: G1202R | Summary: The G1202R mutation is described as a solvent front mutation that contributes to tumor development, as TPX-0131 demonstrated the most potent inhibition of cell proliferation against cells harboring this mutation. Evidence Type: Oncogenic | Mutation: L1196M | Summary: The L1196M mutation is identified as a gatekeeper mutation that contributes to tumor development, with TPX-0131 showing significantly greater potency against this mutation compared to previous ALK inhibitors. Evidence Type: Oncogenic | Mutation: L1198F | Summary: The L1198F mutation is characterized as a hinge region mutation that contributes to tumor development, with TPX-0131 exhibiting high potency against this mutation. Evidence Type: Oncogenic | Mutation: G1269A | Summary: The G1269A mutation is noted as a resistance mutation, with TPX-0131 showing moderate potency against cells harboring this mutation. Evidence Type: Functional | Mutation: I1171N/S/T | Summary: The I1171N/S/T mutations are described in the context of their impact on the potency of TPX-0131, indicating that these mutations alter the molecular function related to drug response.
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
Biochemical characterization of TPX-0131 potency against WT and mutant ALK was assessed in a panel of enzymatic assays with recombinant ALK kinase domains performed at 10 muM ATP (Table 1). TPX-0131 potently inhibited WT
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive
Summary: Evidence Type: Predictive | Mutation: C1156Y | Summary: C1156Y is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy. Evidence Type: Predictive | Mutation: E1210K | Summary: E1210K is inhibited by TPX-0131 with an IC50 of <1 nmol/L, suggesting it correlates with response to this specific therapy. Evidence Type: Predictive | Mutation: S1206C | Summary: S1206C is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy. Evidence Type: Predictive | Mutation: L1198F | Summary: L1198F is inhibited by TPX-0131 with an IC50 of <1 nmol/L, suggesting it correlates with response to this specific therapy. Evidence Type: Predictive | Mutation: L1196M | Summary: L1196M is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy. Evidence Type: Predictive | Mutation: T1151M | Summary: T1151M is inhibited by TPX-0131 with an IC50 of 1 to 2 nmol/L, suggesting it correlates with response to this specific therapy. Evidence Type: Predictive | Mutation: F1174L | Summary: F1174L is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy. Evidence Type: Predictive | Mutation: F1245C | Summary: F1245C is inhibited by TPX-0131 with an IC50 of <1 nmol/L, suggesting it correlates with response to this specific therapy. Evidence Type: Predictive | Mutation: R1275Q | Summary: R1275Q is inhibited by TPX-0131 with an IC50 of <1 nmol/L, indicating a correlation with response to this specific therapy. Evidence Type: Predictive | Mutation: G1202R | Summary: G1202R is inhibited by TPX-0131 with an IC50 of <1 nmol/L, suggesting it correlates with response to this specific therapy. Evidence Type: Predictive | Mutation: G1269A | Summary: G1269A is inhibited by TPX-0131 with an IC50 of 1 to 2 nmol/L, indicating a correlation with response to this specific therapy. Evidence Type: Predictive | Mutation: F1174C | Summary: F1174C is inhibited by TPX-0131 with an IC50 of 1 to 2 nmol/L, suggesting it correlates with response to this specific therapy. Evidence Type: Predictive | Mutation: V1180L | Summary: V1180L is inhibited by TPX-0131 with an IC50 of 1 to 2 nmol/L, indicating a correlation with response to this specific therapy.
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
The most prevalent resistance mutations to second-generation ALK inhibitors (e.g., alectinib, brigatinib) are in the solvent front region (e.g., G1202; ref. 16). Molecular modeling illustrates that second-generation ALK
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Summary: Evidence Type: Predictive | Mutation: G1202 | Summary: The G1202 mutation is associated with resistance to second-generation ALK inhibitors, indicating its relevance in predicting treatment response and resistance to specific therapies. Evidence Type: Oncogenic | Mutation: G1202 | Summary: The G1202 mutation contributes to tumor development by obstructing binding of ALK inhibitors, which is characteristic of oncogenic behavior in cancer progression.
Gene→Variant (gene-first): 238:G1202
Genes: 238
Variants: G1202
TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations
[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
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung c
[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
The correlation of inhibition of ALK phosphorylation (Tyr1282/1283) was evaluated as a function of TPX-0131 plasma exposure analysis using the Ba/F3 CDX model harboring the EML4-ALK fusion with the G1202R/L1196M compound
[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
TGI and the pharmacodynamic modulation of ALK were performed in cell-derived xenograft (CDX) models for clinically relevant ALK mutants that limit the utility of previous generations of ALK inhibitors (e.g. SFM, compound
[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
To confirm the results obtained from the cell proliferation assays, TPX-0131 and select other ALK inhibitors were evaluated in assays measuring pharmacodynamic modulation of ALK (autophosphorylation). TPX-0131 suppressed
[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
In cell proliferation assays, TPX-0131 was the most potent inhibitor against a range of EML4-ALK compound mutations (Table 2). TPX-0131 inhibited six of nine compound mutations with IC50 < 1 nmol/L, had IC50 < 10 nmol/L
[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
To enable comparisons of TPX-0131 with previous generations of ALK inhibitors, a panel of matched cell lines was created that are dependent on ALK resistance mutations found in patients as well as other mutations that ma
[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
Biochemical characterization of TPX-0131 potency against WT and mutant ALK was assessed in a panel of enzymatic assays with recombinant ALK kinase domains performed at 10 muM ATP (Table 1). TPX-0131 potently inhibited WT
[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
The most prevalent resistance mutations to second-generation ALK inhibitors (e.g., alectinib, brigatinib) are in the solvent front region (e.g., G1202; ref. 16). Molecular modeling illustrates that second-generation ALK
[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
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung c
[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
The correlation of inhibition of ALK phosphorylation (Tyr1282/1283) was evaluated as a function of TPX-0131 plasma exposure analysis using the Ba/F3 CDX model harboring the EML4-ALK fusion with the G1202R/L1196M compound
[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
TGI and the pharmacodynamic modulation of ALK were performed in cell-derived xenograft (CDX) models for clinically relevant ALK mutants that limit the utility of previous generations of ALK inhibitors (e.g. SFM, compound
[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
To confirm the results obtained from the cell proliferation assays, TPX-0131 and select other ALK inhibitors were evaluated in assays measuring pharmacodynamic modulation of ALK (autophosphorylation). TPX-0131 suppressed
[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
In cell proliferation assays, TPX-0131 was the most potent inhibitor against a range of EML4-ALK compound mutations (Table 2). TPX-0131 inhibited six of nine compound mutations with IC50 < 1 nmol/L, had IC50 < 10 nmol/L
[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
To enable comparisons of TPX-0131 with previous generations of ALK inhibitors, a panel of matched cell lines was created that are dependent on ALK resistance mutations found in patients as well as other mutations that ma
[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
Biochemical characterization of TPX-0131 potency against WT and mutant ALK was assessed in a panel of enzymatic assays with recombinant ALK kinase domains performed at 10 muM ATP (Table 1). TPX-0131 potently inhibited WT
[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
The most prevalent resistance mutations to second-generation ALK inhibitors (e.g., alectinib, brigatinib) are in the solvent front region (e.g., G1202; ref. 16). Molecular modeling illustrates that second-generation ALK
[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