Efficacy of CBP/p300 Dual Inhibitors against Derepression of KREMEN2 in cBAF-Deficient Cancers.

Abstract

Abstract: The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex is divided into three subcomplexes: cBAF, PBAF, and ncBAF. Constituent genes (e.g., SMARCB1, SMARCA4, SMARCA2, and SS18) of the SWI/SNF complex often harbor genetic abnormalities in various cancers. Previously, we found that histone acetyltransferases CBP/p300 dual inhibitors could be promising treatments for SMARCB1-deficient cancers. We show that treatment with CBP/p300 dual inhibitors causes synthetic lethality in cBAF-deficient cancers such as SMARCA4/SMARCA2-deficient and SS18–SSX fusion cancers. Given the sensitivity to CBP/p300 dual inhibitors and their commonality with SWI/SNF subcomplexes containing each subunit, CBP/p300 dual inhibitors could be promising treatments for cancers harboring abnormalities in constituent genes included in the entire cBAF subcomplex. Because SMARCA4/SMARCA2-deficient and SS18–SSX fusion cancer cells depend on transcriptional upregulation of KREMEN2 due to SMARCA4/SMARCA2 deficiency and SS18–SSX fusion, we clarified that synthetic lethality is induced by repressing expression of KREMEN2 by simultaneous inhibition of CBP/p300. In addition, simultaneous inhibition of CBP/p300 led to transcriptional downregulation of KREMEN2, followed by apoptosis induction via KREMEN1. Furthermore, treatment with CBP/p300 dual inhibitor suppressed the growth of xenografts derived from SMARCA4/SMARCA2-deficient and SS18–SSX fusion cancer cells, resulting from repression of KREMEN2 and induction of apoptosis. Thus, CBP/p300 dual inhibitors could be promising for SMARCA4/SMARCA2-deficient lung cancer and SS18–SSX fusion synovial sarcoma, which are entirely deficient in the cBAF complex.

Significance: In this study, we clarified that the cBAF subcomplex is deficient in the SWI/SNF complex, resulting in dependency on the CBP/p300 paralog pair. Simultaneous inhibitors of the CBP/p300 paralog pair show promise for cBAF-deficient lung cancer, as well as rare cancers such as malignant rhabdoid tumors, epithelioid sarcomas, and synovial sarcomas.