Co-repressor of Repressor Element-1 Silencing Transcription complex (CoREST)

The Co-repressor of Repressor Element-1 Silencing Transcription (CoREST) complex is a multi-protein epigenetic regulator that plays a pivotal role in gene silencing by coordinating histone deacetylation and demethylation [11]. It has been identified as a key synthetic lethal target for cancers harboring loss-of-function mutations in the STK11 (LKB1) tumor suppressor gene, which are prevalent in approximately 15-20% of non-small cell lung cancers (NSCLC) and other solid tumors [17, 22]. STK11-mutant tumors are typically immune-cold and resistant to checkpoint inhibitors due to suppressed expression of immunomodulatory genes [11]. Inhibition of the CoREST complex, specifically the HDAC1 subunit within this complex, reverses this immune evasion by inducing the expression of chemokines and cell adhesion molecules that promote T-cell infiltration and antigen presentation [17]. This therapeutic strategy, exemplified by the clinical-stage candidate TNG260, aims to sensitize STK11-deficient tumors to anti-PD-1/PD-L1 therapies, potentially overcoming a major mechanism of primary resistance in precision oncology [22].

Other names

RCOR1 complexCoREST deacetylase complexTarget 3 (Tango Therapeutics)Undisclosed Target 3

Selective inhibition of HDAC1 within the CoREST complex to reverse immune evasion in STK11-mutant tumors [17].