Proteasome Inhibitors Interact Synergistically with BCL2, Histone Deacetylase, BET, and Jak Inhibitors against Cutaneous T-Cell Lymphoma Cells

Abstract

Cutaneous T-cell lymphoma (CTCL) is often refractory to treatment at advanced stages with blood involvement ( Dummer et al., 2021 Dummer R. Vermeer M.H. Scarisbrick J.J. Kim Y.H. Stonesifer C. Tensen C.P. et al. Cutaneous T cell lymphoma. Nature Reviews Disease Primers. 2021; 7: 61 Crossref PubMed Scopus (22) Google Scholar ). We have previously revealed the synergistic cytotoxic effects of inhibiting BCL2, HDAC, BET, and/or JAK in patient-derived CTCL cells and CTCL cell lines, suggesting potential advantages of a spectrum of combination treatment strategies for this disease ( Cyrenne et al., 2017 Cyrenne B.M. Lewis J.M. Weed J.G. Carlson K.R. Mirza F.N. Foss F.M. et al. Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients. Blood. 2017; 130: 2073-2083 Crossref PubMed Scopus (36) Google Scholar , Kim et al., 2018 Kim S.R. Lewis J.M. Cyrenne B.M. Monico P.F. Mirza F.N. Carlson K.R. et al. BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition. Oncotarget. 2018; 9: 29193-29207 Crossref PubMed Scopus (35) Google Scholar , Yumeen et al., 2020 Yumeen S. Mirza F.N. Lewis J.M. King A.L.O. Kim S.R. Carlson K.R. et al. JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL. Blood Adv. 2020; 4: 2213-2226 Crossref PubMed Scopus (19) Google Scholar ). Proteasome inhibitors target multiple pathways including protein degradation to cause cytotoxicity and have been utilized in other hematologic malignancies. They have demonstrated efficacy as a single agent in a small phase II trial of patients with relapsed or refractory CTCL ( Zinzani et al., 2007 Zinzani P.L. Musuraca G. Tani M. Stefoni V. Marchi E. Fina M. et al. Phase II Trial of Proteasome Inhibitor Bortezomib in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma. Journal of Clinical Oncology. 2007; 25: 4293-4297 Crossref PubMed Scopus (236) Google Scholar ), as well as in limited combinations during preclinical studies ( Yumeen et al., 2020 Yumeen S. Mirza F.N. Lewis J.M. King A.L.O. Kim S.R. Carlson K.R. et al. JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL. Blood Adv. 2020; 4: 2213-2226 Crossref PubMed Scopus (19) Google Scholar ) and early clinical trials ( Holkova et al., 2017 Holkova B. Yazbeck V. Kmieciak M. Bose P. Ma S. Kimball A. et al. A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. Leuk Lymphoma. 2017; 58: 1349-1357 Crossref PubMed Scopus (15) Google Scholar ). Herein, we share our expanded preclinical assessment of the synergistic activity of proteasome inhibitors when used with the BCL2 inhibitor venetoclax, HDAC inhibitor vorinostat, BET inhibitor mivebresib, or JAK inhibitor fedratinib. We reveal that the cytotoxic effects from combination treatment were greater than additive when assessed in patient-derived CTCL cells. Furthermore, we demonstrate an increase in apoptosis pathway activation with combination treatment and explore the gene expression changes underlying these synergistic effects.