Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer

Nyree Crawford, Katie J Stott, Tamas Sessler, Christopher McCann, William McDaid, Andrea Lees, Cheryl Latimer, Jennifer P Fox, Joanne M Munck, Tomoko Smyth, Alpesh Shah, Vanessa Martins, Mark Lawler, Philip D Dunne, Emma M Kerr, Simon S McDade, Vicky M Coyle, Daniel B Longley, Nyree Crawford, Katie J Stott, Tamas Sessler, Christopher McCann, William McDaid, Andrea Lees, Cheryl Latimer, Jennifer P Fox, Joanne M Munck, Tomoko Smyth, Alpesh Shah, Vanessa Martins, Mark Lawler, Philip D Dunne, Emma M Kerr, Simon S McDade, Vicky M Coyle, Daniel B Longley

Abstract

Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)-based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance. A novel IAP antagonist tolinapant (ASTX660) potently and rapidly downregulated cIAP1 in colorectal cancer models, demonstrating its robust on-target efficacy. In cells co-cultured with TNFα to mimic an inflammatory tumor microenvironment, tolinapant induced caspase-8-dependent apoptosis in colorectal cancer cell line models; however, the extent of apoptosis was limited because of inhibition by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinapant-induced apoptosis was augmented by FOLFOX in human colorectal cancer and murine organoid models in vitro and in vivo, due (at least in part) to FOLFOX-induced downregulation of class I histone deacetylases (HDAC), leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, the effects of FOLFOX could be phenocopied using the clinically relevant class I HDAC inhibitor, entinostat, which also induced acetylation of Ku70 and FLIP downregulation. Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8-proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.

Trial registration: ClinicalTrials.gov NCT03871959.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Correlation between high cIAP1/2 expression and prognosis. Analysis of patients with stage III MSS who received adjuvant fluorouracil-based treatment extracted from GSE39582 cohort. A, Kaplan–Meier plots of 5-year OS. Graphs comparing the difference in survival probability based on BIRC2 and BIRC3 expression levels alone. Results are shown with the log-rank test, the HR with its 95% confidential interval and the Wald test of significance. B–E, Difference of pathway activation by ssGSEA (B) and cell type profiling (D) by xCELL between cIAP1 or cIAP2 high and low expressing patients was assessed by one-way ANOVA model. Numbers shown are the calculated P values. Heatmap were drawn showing the Z-scores of the significantly different ssGSEA pathways (C) and immune or stroma infiltration by xCELL (E).
Figure 2.
Figure 2.
Sensitivity of colorectal cancer cell lines to IAP inhibitor, tolinapant. A, Cell viability assay in 36 colorectal cancer cell line panel following 72 hours treatment with tolinapant (tolin; 10-point assay 0.0005–10 μmol/L) alone and in combination with TNFα (1 ng/mL), represented as relative activity area (%), calculated as (experimental AUC/max AUC possible). Cell lines categorized as sensitive to tolinapant/TNFα are highlighted in green, intermediate in white, and resistant in orange. B, Western blot analysis of basal expression of FLIP(L), FLIP(S), Mcl-1, cIAP1, cIAP2, XIAP, BAX, SMAC, RIPK1, FADD, procaspase-8, procaspase-10, RIPK3 and MLKL and β-actin in a panel of colorectal cancer cell lines. C, Cell surface expression of TNFR1 in DLD1, SW620, LoVo, HT29, and HCT116 cell lines, represented as % of TNFR1-positive cells compared with an IgG isotype control. D, Western blot analysis of cIAP1, cIAP2, XIAP, and β-actin in HCT116, HT29, and DLD-1 cells following treatment with 1 μmol/L, 100 nmol/L, 10 nmol/L, 1 nmol/L, and 0.1 nmol/L tolinapant for 24 hours. E, Western blot analysis of RIPK1 and procaspase-8 following immunoprecipitation of caspase-8 from HCT116, HT29, and DLD-1 cells treated with 1 ng/mL TNFα, 1 μmol/L tolinapant and a combination of TNFα/tolinapant for 3 hours in the presence of 20 μmol/L z-VAD-fmk. An IgG isotype control was used as a control. F, Annexin V/PI analysis in HCT116, HT29, and DLD-1 cells following treatment with 1 ng/mL TNFα, 1 μmol/L tolinapant, or a combination of TNFα/tolinapant for 24 hours. G, Tumor volume (mm3) in HCT116, HT29, and DLD-1 xenograft models treated with vehicle and 16 mg/kg tolinapant. Data show mean tumor volume per treatment group per timepoint ± SEM (HCT116; vehicle n = 10, tolinapant n = 10, HT29; vehicle n = 7, tolinapant n = 7, SW620; vehicle n = 10, tolinapant n = 12). Results were compared using a two-tailed Student t test, *, P < 0.05; **, P < 0.01; and ***, P < 0.001
Figure 3.
Figure 3.
Tolinapant synergizes with chemotherapy. A, Annexin V/PI analysis in HCT116, SW620, and HT29 cells treated with 1 ng/mL TNFα, 1 μmol/L tolinapant, or a combination of tolinapant/TNFα in the presence and absence of 5 μmol/L 5FU and 1 μmol/L oxaliplatin (OX) for 72 hours. B, Western blot analysis of PARP, cIAP2, cIAP1, XIAP, FLIP(L), FLIP(S), and β-actin in HCT116, SW620, and HT29 cells treated with 5 μmol/L 5FU and 1 μmol/L oxaliplatin (FOLFOX), 1 μmol/L tolinapant and a combination of FOLFOX/tolinapant (COMBO) for 24 and 48 hours. C, Pictures from AKP and AK organoids treated with 1 μmol/L tolinapant/1 ng/mL TNFα (tolin/TNF), 5 μmol/L 5FU and 1 μmol/L oxaliplatin (FF) or combination (COMBO) for 72 hours. Diameter in AU from AKP (n = 75 for each treatment group) and AK (n = 75 for each treatment group) organoids treated with 1 μmol/L tolinapant/1 ng/mL TNFα (tolin/TNF), 5 μmol/L 5FU and 1 μmol/L oxaliplatin (FOLFOX) or combination (COMBO) for 72 hours. D, Cell viability assays in AKP and AK organoids treated with 1 μmol/L tolinapant/1 ng/mL TNFα (tolin/TNF), 5 μmol/L 5FU and 1 μmol/L oxaliplatin (FOLFOX) or combination (COMBO) for 72 hours. E, Western blot analysis of basal expression of cIAP1, p53, and β-actin in AK and AKP organoids. Western blot analysis of cIAP1 and β-actin in AK and AKP organoids treated with 1 μmol/L tolinapant for 24 hours. F, Tumor volume (mm3) of AKP organoids transplanted into C57BL/6 mice treated with vehicle (n = 3), 5FU (10 mg/kg) + oxaliplatin (1 mg/kg; FOLFOX; n = 4), tolinapant (16 mg/kg; n = 4) and combination (n = 4). Data show mean tumor volume per treatment group per timepoint ± SEM. G, Densitometry from Western blot analysis of cIAP1 normalized to β-actin in AKP organoids transplanted into C57BL/6 mice and treated with vehicle (n = 3), 5FU (10 mg/kg) + oxaliplatin (1 mg/kg; FOLFOX; n = 4), tolinapant (16 mg/kg; n = 4), and combination (n = 3). Results were compared using a two-tailed Student t test, *, P < 0.05; **, P < 0.01; and ***, P < 0.001.
Figure 4.
Figure 4.
Role of FLIP in determining sensitivity to tolinapant. A, Expression of caspase-8 and FLIP mRNA [log2 (TPM (transcripts per million) + 1] in colorectal cancer cell lines categorized as sensitive or resistant to tolinapant/TNFα in the cell line screen in Fig. 2A. B, Annexin V/PI analysis in HCT116, SW620, HT29, DLD-1, and LoVo cells transfected with control (SCR) and FLIP(T) siRNA for 24 hours prior to treatment with 1 μmol/L tolinapant and 1 ng/mL TNFα for a further 24 hours. C, Cell viability assays in HCT116, SW620, HT29, DLD-1, and LoVo cells transfected with control (SCR) and FLIP(T) siRNA for 6 hours prior to treatment with 1 μmol/L tolinapant and 1 ng/mL TNFα for a further 24 hours. D, Western blot analysis of PARP, FLIP(L), FLIP(S), cIAP1, and β-actin and in HCT116, SW620, and HT29 cells transfected with control (SCR) and FLIP(T) siRNA for 24 hours prior to treatment with 1 μmol/L tolinapant and 1 ng/mL TNFα for a further 24 hours. Results were compared using a two-tailed Student t test, *, P < 0.05; **, P < 0.01; and ***, P < 0.001.
Figure 5.
Figure 5.
Mechanism of chemotherapy-induced sensitization to tolinapant. A, Western blot analysis of FLIP(L), FLIP(S), and β-actin in HCT116 cells retrovirally overexpressing pbabe empty vector (EV), pbabe FLIP(S), pbabe FLIP(S) F114A, and pbabe FLIP(L). B, Annexin V/PI analysis of in HCT116 cells retrovirally overexpressing pbabe empty vector (EV), pbabe FLIP(S), pbabe FLIP(S) F114A, and pbabe FLIP(L) following treatment with 1 μmol/L tolinapant/1 ng/mL TNFα, 5 μmol/L 5FU, and 1 μmol/L oxaliplatin (FOLFOX) or combination for 48 hours. C, Western blot analysis of PARP, cIAP1, FLIP(L), FLIP(S), procaspase-8, procaspase-10, and β-actin in HCT116 WT and HCT116 caspase-8 KO cells treated with 1 μmol/L tolinapant/1 ng/mL TNFα (tolin/TNFα), 5 μmol/L 5FU and 1 μmol/L oxaliplatin (FF) or combination for 48 hours. D, Annexin V/PI analysis in HCT116 WT and HCT116 caspase-8 KO cells treated with 1 μmol/L tolinapant/1 ng/mL TNFα, 5 μmol/L 5FU, and 1 μmol/L oxaliplatin (FOLFOX) or combination for 72 hours. E, Western blot analysis of procaspase-10, PARP, cleaved caspase-3, FLIP(L), FLIP(S), cIAP1, and β-actin in HCT116 and DLD1 cells transfected with control (SCR) and caspase-10 (siC10) siRNA for 24 hours prior to treatment with 1 μmol/L tolinapant and 1 ng/mL TNFα for a further 24 hours. F, Caspase-3/7 activity assay in HCT116 cells transfected with control (SCR) and caspase-10 siRNA (siC10) for 24 hours prior to treatment with 1 μmol/L tolinapant and 1 ng/mL TNFα (tolin/TNFα) for a further 24 hours. G, Western blot analysis of procaspase-10, procaspase-8, and β-actin in HCT116 WT, HCT116 caspase-8 KO, HCT116 caspase-10 KO and HCT116 caspase-8/caspase-10 DKO cells, and Annexin V/PI analysis in HCT116 WT and HCT116 caspase-8 KO, HCT116 caspase-10 KO and HCT116 caspase-8/caspase-10 DKO cells treated with 1 μmol/L tolinapant/1 ng/mL TNFα, 5 μmol/L 5FU and 1 μmol/L oxaliplatin (FOLFOX) or combination for 48 hours. H, Western blot analysis of HDAC1, HDAC2, HDAC3, and β-actin in HCT116 WT and HCT116 caspase-8 KO cells treated with 1 μmol/L tolinapant/1 ng/mL TNFα (tolin/TNFα), 5 μmol/L 5FU, and 1 μmol/L oxaliplatin (FF) or combination for 48 hours. I, Western blot analysis of Ku70 following immunoprecipitation of acetylated lysine (AcK) from HCT116 cells treated with 5 μmol/L 5FU and 1 μmol/L oxaliplatin (FOLFOX) for 24 hours. An IgG isotype control was used as a control. J, Western blot and caspase-3/7 activity analyses of Ku70, FLIP(L), FLIP(S), procaspase-10, PARP, cIAP1, CIAP2, XIAP, and β-actin and in HCT116 cells transfected with control (SCR) and Ku70 siRNA (siKU70) for 24 hours prior to treatment with 1 μmol/L tolinapant and 1 ng/mL TNFα (tolin/TNFα) for a further 24 hours.
Figure 6.
Figure 6.
Necroptotic cell death induced by tolinapant in RIPK3-expressing colorectal cancer cells. A, Cell viability assays in HT29 caspase-8 WT and HT29 caspase-8 KO cells pretreated with 2.5 μmol/L entinostat for 24 hours then addition of 1 μmol/L tolinapant and 1 ng/mL TNFα for a further 24 hours. B, Western blot analysis of PARP, p-MLKL(Ser358), total MLKL, p-RIPK3(Ser227), total RIPK3, p-RIPK1(Ser166), total RIPK1, cIAP1, caspase-8, and β-actin in HT29 caspase-8 WT and HT29 caspase-8 KO cells 24 hours following treatment with 1 μmol/L tolinapant and 1 ng/mL TNFα. C, PI analysis in HT29 caspase-8 WT and HT29 caspase-8 KO cells pretreated for 30 minutes with 10 μmol/L z-VAD and 2 μmol/L necrosulfonamide then addition of 1 μmol/L tolinapant and 1 ng/mL TNFα for 24 hours. D, Annexin V/PI analysis in HT29 cells pretreated with 10 μmol/L z-VAD, 5 μmol/L emricasan or 10 μmol/L emricasan for 30 minutes then addition of 1 μmol/L tolinapant and 1 ng/mL TNFα for 24 hours. E, Western blot analysis of p-MLKL(Ser358), total MLKL, p-RIPK3(Ser227), total RIPK3, p-RIPK1 (Ser166), total RIPK1, cIAP1, and β-actin in HT29 cells pretreated with 10 μmol/L emricasan for 30 minutes then addition of 1 μmol/L tolinapant and 1 ng/mL TNFα for 24 hours. F, Pictures from AK and AKP organoids pretreated with 10 μmol/L emricasan for 30 minutes then addition of 1 μmol/L tolinapant and 1 ng/mL TNFα for 48 hours. G, Western blot analysis of p-RIPK3 (Thr231/Ser232), total RIPK3, cIAP1, and β-actin in AKP organoids pretreated with 10 μmol/L necrostatin-1 and 10 μmol/L emricasan (Emri) for 30 minutes before the addition of 1 μmol/L tolinapant and 1 ng/mL TNFα (tolin/TNF) for 24 hours. Results were compared using a two-tailed Student t test, *, P < 0.05; **, P < 0.01; and ***, P < 0.001.

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