LAUSR

Targeting of bromoand extra-terminal domain (BET) motifs has been a heavily investigated area for therapeutic intervention for some time, and despite intensive efforts have yet to be approved for clinical use.[1] Andwhile a significant quantity of research has focussed on the potential to therapeutically target cancer, other indications have emerged formanyother non-cancerous settings for example in targeting vitiligo, diabetes, cardiovascular events and drug-induced neurobehavioral responses to addictive substances such as cocaine. Despite these advances, the consensus remains that BETi as single agents are insufficient to achieve meaningful clinical responses, and may best be used in a combinatorial setting. Issues such as intratumoural epigenetic heterogeneity can affect efficacy, while the identification of good biomarkers both predictive of sensitivity (e.g., loss of BAP1, overexpression of MYC) and for resistance (e.g., SPOP mutations, KRASmutations) to BETi are critical.[1] In a Hypotheses article published in BioEssays in 2018, Chatterjee and Bohmann suggested that targeting the oxidative stress pathway may be useful to specifically target cancer stem cell niches in cancers which have developed resistance to BETi.[2] And indeed in 2019, the BETi OTX015 was shown to impair leukaemic stem cell function in defined oncogenic sub-groups of acute myeloid leukaemias (AMLs). However, a study in small-cell lung cancer (SCLC) by Lv et al.[3] that metabolic remodelling of NRF2 in response to oxidative stress contributes to BETi resistance in SCLC suggesting that all may not be as it seems. However, significant links between BETi and NRF2 have emerged in the field of immunotherapy. Key to this has been the finding that NRF2 is a key regulator of PD-L1 via CUL3/BRD4.[4] BETi have since been found to sensitize tumour cells to the cytolytic activity of CD8+ T cells, in a manner involving increased sensitivity to TNF. Whilst this in itself is of great interest, another study in AML found that BETi could effectively rescue both T cell exhaustion and immune cell blockade resistance.[5] Themechanismposited suggests that BETi actmechanistically to relieve the repression of progenitor programs in exhausted CD8+ T cells and restore and maintain a pool of anti-PD1 responsive CD8+ T cells.[5] Indeed an earlier study in chronic lymphocytic leukaemia (CML), also found that BETi could reinvigorate exhausted T cells,[6] andmoreoverhadpotential applicabilitywith respect toCD19targeted chimeric antigen receptor (CAR)-T therapy. In this study, the authors found that for a subset of patients who relapsed upon CAR-Tbased therapy, BET proteins were associated with the loss of the CAR, and this loss could be subsequently relieved by the use of BETi. Whilst in the current clinical setting, BETi remain for use as single agents, they continue to remain an exciting prospect. As more knowledge emerges around themechanisms of resistance toBETi, and newer generation compounds such as proteolysis targeting chimeras (PROTACs) along with new delivery platforms, their routine use in the clinic may become viable, especially in the area of immunotherapy.