BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition

Abstract

While several systemic therapies are approved for cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma of skin-homing T cells that may involve lymph nodes and peripheral blood in advanced stages, relapses are common. Mutational analysis of CTCL cells has revealed frequent amplification of the MYC oncogene, and bromodomain and extraterminal (BET) protein inhibitors have been shown to repress MYC expression in various malignancies. Towards a potential novel therapy, we thus sought to examine the effect of BET inhibition on CTCL cells in vitro. Each of the four tested BET inhibitors (JQ1, ABBV-075, I-BET762, CPI-0610) consistently induced dose-dependent decreases in viability of isolated patient-derived CTCL cells and established CTCL cell lines (MyLa, Sez4, HH, Hut78). This effect was synergistically potentiated by combination of BET inhibition with BCL2 inhibition (e.g. venetoclax) or histone deacetylase (HDAC) inhibition (e.g. vorinostat or romidepsin). There was also a marked increase in caspase 3/7 activation when JQ1 was combined with either vorinostat or romidepsin, confirming that the observed synergies are due in major part to induction of apoptosis. Furthermore, MYC and BCL2 expression were each synergistically repressed when CTCL cells were treated with JQ1 plus HDAC inhibitors, suggesting cooperative activities at the level of epigenetic regulation. Taken together, these data indicate that targeting BET proteins in CTCL represents a promising novel therapeutic strategy that may be substantially potentiated by combination with BCL2 or HDAC inhibition.

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…Kim et al showed that the cytotoxic effects induced by BETi (such as JQ1 42 or ABBV‐075 43 ) resulted synergistically amplified by either HDACi (vorinostat 3 or romidepsin 4 ) or BCL2i (venetoclax 44 ) (Combination J, Figure ) in the majority of both CTCL cell lines (MyLa, Sez4, HH, and Hut78) and CTCL tumor samples derived from patients who had previously tried both single and multiple therapies without success. In this study, synergistic effects on the modulation of the genes BCL2 and MYC, and of genes encoding for proapoptotic and cell cycle regulation factors (BIM, CDKN1A , and p21 ) , as well as a lower level of BCL2L1 expression were observed . In addition, a substantial increase in caspase 3/7 activation was registered when the BETi JQ1 42 was combined with either romidepsin 4 or vorinostat 3 , confirming that the observed synergies are mainly due to apoptosis induction …”

“…In this study, synergistic effects on the modulation of the genes BCL2 and MYC, and of genes encoding for proapoptotic and cell cycle regulation factors (BIM, CDKN1A, and p21), as well as a lower level of BCL2L1 expression were observed. 159 In addition, a substantial increase in caspase 3/7 activation was registered when the BETi JQ1 42 was combined with either romidepsin 4 or vorinostat 3, confirming that the observed synergies are mainly due to apoptosis induction. 159 Preclinical studies conducted by Wang et al 175 demonstrated the therapeutic potential of the combination of EZH2i and HDACi against small cell carcinoma of the ovary hypercalcemic type (SCCOHT), a rare but extremely lethal cancer that interests mainly young women.…”

“…Recently, other preclinical studies based on the simultaneous administration of BETi and HDACi in melanoma cells as well as in murine models of pancreatic ductal adenocarcinoma have been described recently . In 2018, the combination of the BETi JQ1 42 and romidepsin 4 (Combination I, Figure ) in urothelial carcinoma (UC) inhibited cell cycle progression, suppressed clonogenic growth, and induced apoptosis.…”

“…In this study, synergistic effects on the modulation of the genes BCL2 and MYC, and of genes encoding for proapoptotic and cell cycle regulation factors (BIM, CDKN1A , and p21 ) , as well as a lower level of BCL2L1 expression were observed . In addition, a substantial increase in caspase 3/7 activation was registered when the BETi JQ1 42 was combined with either romidepsin 4 or vorinostat 3 , confirming that the observed synergies are mainly due to apoptosis induction …”

“…146 A lot of clinical studies have been conducted focusing on RAS effectors, in particular on inhibitors of PI3K signaling pathways 147 and of mitogen-activated protein kinase (MAPK) such as MEK inhibitors, 147 Recently, other preclinical studies based on the simultaneous administration of BETi and HDACi in melanoma cells as well as in murine models of pancreatic ductal adenocarcinoma have been described recently. [156][157][158][159] In 2018, the combination of the BETi JQ1 42 and romidepsin 4 (Combination I, Figure 3 deletions. [161][162][163][164][165] To date, CTCL is generally considered incurable.…”