CREB-binding protein and E1A-binding protein p300 and Poly(ADP-ribose) polymerase 1 and Poly(ADP-ribose) polymerase 2 (CBP/p300 and PARP1/2)

CRPC cells with combined CBP/EP300 and PARP1/2 dependence refers to a therapeutic axis in advanced prostate cancer where the survival of Castration-Resistant Prostate Cancer (CRPC) cells is jointly maintained by transcriptional co-activators and DNA repair enzymes. CREB-binding protein (CBP) and E1A-binding protein p300 (EP300) are paralogous histone acetyltransferases that facilitate the expression of the Androgen Receptor (AR) and its constitutively active variants, such as AR-V7, which drive resistance to standard hormonal therapies (Welti et al., 2021, Cancer Discovery). Poly(ADP-ribose) polymerase 1 and 2 (PARP1/2) are critical enzymes for the repair of single-strand DNA breaks via the base-excision repair pathway (UniProt P09874). Pharmacological inhibition of the CBP/p300 bromodomain (e.g., with CCS1477) has been shown to downregulate the expression of key homologous recombination repair (HRR) genes, effectively inducing a BRCAness phenotype (CellCentric, 2023). This molecular vulnerability renders the cells hypersensitive to PARP inhibitors, which trap PARP on DNA and cause lethal double-strand breaks in the absence of functional HRR. This dual-targeting strategy aims to overcome resistance to second-generation anti-androgens and expand the clinical utility of PARP inhibitors to patients who lack innate DNA repair mutations. Consequently, this combined dependence represents a high-value target for synergistic drug combinations in the treatment of metastatic CRPC.

Other names

CBP/p300-PARP axisCBP/EP300 and PARP1/2 co-dependenceCBP/p300 and PARP synergy in CRPCCBP/p300-PARP synthetic lethality

Dual inhibition of transcriptional co-activation and DNA damage repair; CBP/p300 inhibition induces a BRCAness phenotype by downregulating HRR genes, which synergistically sensitizes cells to the DNA-damaging effects of PARP1/2 inhibition.