Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor Carfilzomib (CFZ) were examined in non-Hodgkin’s lymphoma models, including diffuse large B-cell (DLBCL), mantle cell (MCL) and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with CFZ and ricolinostat increased reactive oxygen species (ROS), while the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34+ cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by CFZ. shRNA knock-down of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced CFZ/ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to CFZ and ricolinostat also markedly down-regulated the cargo-loading protein HR23B. Moreover, HR23B knock-down significantly increased CFZ- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with CFZ and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that CFZ and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL.
Summary
The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo‐HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo‐HCT between 2008 and 2019. Non‐relapse mortality (NRM), disease relapse/progression (REL), progression‐free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow‐up of survivors was 62 (3–148) months. The 1‐year NRM was 18%. The 5‐year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6–4.8; p < 0.001) and refractory disease at allo‐HCT (HR 3.2, 95% CI 1.6–6.2; p < 0.001) were predictive of inferior OS. Similarly, African‐American race (HR 2.1, 95% CI 1.3–3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2–5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2–4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo‐HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo‐HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo‐HCT are driven by differences in disease biology or disparities in post allo‐HCT care, or both, requires further investigation.
<p>Supplementary Figures and Tables. Fig 1: Synergistic interactions between CFZ and ACY1215 lead to induction of apoptosis in a time-dependent manner. Fig 2: Knocking down HDAC6 expression by shRNA or pharmacologic inhibition by ACY1215 or Tubastatin A potentiates proteasome inhibitor lethality. Fig 3: Combined CFZ/ACY1215 exposure activates stress pathways and increases DNA damage in SUDHL16 cell. Fig 4: Pre-treatment of cells with pan-caspase inhibitor BOC does not protect JNK activation, induction of DNA damage and inactivation of ERK. Fig 5: Knocking down HDAC6 expression by shRNA recapitulate signaling events when treated with ACY1215 alone similar to combined treatment of CFZ+ ACY1215 to untransfected cells. Fig 6: CFZ and ACY1215 interact synergistically in bortezomib-resistant DLBCL and MCL cells. Fig 7: Constitutive MEK/ERK phosphorylation does not protect SUDHL4 cells from the ACY1215+CFZ regimen. Fig 8: Knocking down of Histone1.2 circumvent the lethality of ACY1215+CFZ drug regimen in U2932 cells. Sup Table 1: Addition of ACY1215 to CFZ does not enhance inhibition of chymotryptic activity in DLBCL cells. Sup Table 2: Combined ACY1215t/CFZ exposure leads to G2M arrest of DLBCL cells.</p>
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