Proteomic changes during therapy with pirtobrutinib. Cells were isolated from patients’ peripheral blood samples (n = 18), which were collected before pirtobrutinib treatment (C1D1) and at the indicated time points (C1D8, C2D1, and C4D1). Total proteins in the samples were isolated and assayed using RPPA. Differential protein analysis between the time points was performed using t tests for the BTK-WT and BTK-mutated cohorts separately. No significant differences in protein expression were observed after adjusting for multiple testing. (A) A heat map of the top 20 differentially expressed proteins by log fold change at 1 month after therapy (C2D1) in comparison with that before therapy (C1D1) in patients with WT BTK (n = 7). The numbers at the bottom of the heat map are patient identifiers that were provided with the patient characteristics in Table 1. (B) A heat map of the top 20 differentially expressed proteins by log fold change at 1 month after therapy (C2D1) in comparison with that before treatment (C1D1) in patients with mutated BTK (n = 11). The numbers at the bottom of the heat map are patient identifiers that were provided with the patient characteristics in Supplemental Table 1. (C) One-way analysis of variance was used to identify protein levels that differed significantly among the time points of therapy with pirtobrutinib in the BTK-WT and BTK-mutated cohorts separately. The common proteins (top 20 by P value) across both cohorts are shown in the heat map. The protein data for the cohorts are separated by the yellow line, and the corresponding patient identifiers are provided at the bottom of the heat map. (D) Box plots comparing the baseline (C1D1) protein expression levels with that at C1D8 and C2D1 in the BTK-mutated group. Significant differences in proteins were plotted. The top 2 rows are proteins that were significantly downregulated and that were linked to the BCR pathway, metabolism, and cell survival or proliferation. The bottom row is proteins that were significantly upregulated during treatment with pirtobrutinib, including several proteins and phosphoproteins, including Rictor (T1135), PIP4K2B, PAK4, 14-3-3 Zeta, p27 (T157), Smad4, PKCαβII (T638/T641), and PKCβ2 (S660).

Proteomic changes during therapy with pirtobrutinib. Cells were isolated from patients’ peripheral blood samples (n = 18), which were collected before pirtobrutinib treatment (C1D1) and at the indicated time points (C1D8, C2D1, and C4D1). Total proteins in the samples were isolated and assayed using RPPA. Differential protein analysis between the time points was performed using t tests for the BTK-WT and BTK-mutated cohorts separately. No significant differences in protein expression were observed after adjusting for multiple testing. (A) A heat map of the top 20 differentially expressed proteins by log fold change at 1 month after therapy (C2D1) in comparison with that before therapy (C1D1) in patients with WT BTK (n = 7). The numbers at the bottom of the heat map are patient identifiers that were provided with the patient characteristics in Table 1. (B) A heat map of the top 20 differentially expressed proteins by log fold change at 1 month after therapy (C2D1) in comparison with that before treatment (C1D1) in patients with mutated BTK (n = 11). The numbers at the bottom of the heat map are patient identifiers that were provided with the patient characteristics in Supplemental Table 1. (C) One-way analysis of variance was used to identify protein levels that differed significantly among the time points of therapy with pirtobrutinib in the BTK-WT and BTK-mutated cohorts separately. The common proteins (top 20 by P value) across both cohorts are shown in the heat map. The protein data for the cohorts are separated by the yellow line, and the corresponding patient identifiers are provided at the bottom of the heat map. (D) Box plots comparing the baseline (C1D1) protein expression levels with that at C1D8 and C2D1 in the BTK-mutated group. Significant differences in proteins were plotted. The top 2 rows are proteins that were significantly downregulated and that were linked to the BCR pathway, metabolism, and cell survival or proliferation. The bottom row is proteins that were significantly upregulated during treatment with pirtobrutinib, including several proteins and phosphoproteins, including Rictor (T1135), PIP4K2B, PAK4, 14-3-3 Zeta, p27 (T157), Smad4, PKCαβII (T638/T641), and PKCβ2 (S660).

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