BMAL2 is a druggable target for ovarian clear cell carcinoma (OCCC)

Ovarian clear cell carcinomas (OCCC), particularly cases that retain wild-type AT-rich interactive domain 1 A (ARID1A) expression (approximately 50% of the OCCC cases), are chemoresistant and lack specific therapies. We identified BMAL2 as a critical OCCC oncogene that promotes tumorigenesis by preventing endogenous DNA damage. BMAL2 depletion altered the expression of genes encoding DNA damage repair proteins, including RAD51, a core enzyme of the homologous recombination (HR) pathway. This led to DNA double-stranded break accumulation, decreased cell viability and reduced tumor growth. This dependence on BMAL2 to maintain DNA integrity and cell viability can be a new route to suppress OCCC. Consistent with this idea, we found that GW833972A, a cannabinoid receptor agonist, bound BMAL2 with high affinity and facilitated its protein degradation. This in turn reduced RAD51 expression, leading to an accumulation of DNA damage, decreased cell viability and reduced OCCC tumor growth. GW833972A is effective by itself at high dose and can also be used at lower dosages to enhance the effectiveness of Poly (ADP-ribose) polymerase inhibitor (PARPi) treatments in BMAL2-expressing OCCC. Together, our findings reveal an essential oncogenic role of BMAL2 and demonstrate that it is an appealing therapeutic target, especially for ARID1A-wt OCCC. BMAL2 depletion, or BMAL2 degradation induced by the small molecule GW833972A, led to DNA damage accumulation, decreased cell viability and reduced tumorigenesis of ovarian clear cell carcinoma (OCCC), indicating that BMAL2 is an appealing therapeutic target for treating this malignant disease. High BMAL2 expression is correlated with poor clinical outcome in ovarian cancers, including OCCC. BMAL2-mediated DNA integrity maintenance is an OCCC subtype-specific regulatory mechanism critical for OCCC tumor growth. GW833972A bound to BMAL2 protein and facilitated its degradation via the proteasome system. GW833972A can effectively target BMAL2-expressing cancer cells with little adverse effect on normal cells. High BMAL2 expression is correlated with poor clinical outcome in ovarian cancers, including OCCC. BMAL2-mediated DNA integrity maintenance is an OCCC subtype-specific regulatory mechanism critical for OCCC tumor growth. GW833972A bound to BMAL2 protein and facilitated its degradation via the proteasome system. GW833972A can effectively target BMAL2-expressing cancer cells with little adverse effect on normal cells. BMAL2 depletion, or BMAL2 degradation induced by the small molecule GW833972A, led to DNA damage accumulation, decreased cell viability and reduced tumorigenesis of ovarian clear cell carcinoma (OCCC), indicating that BMAL2 is an appealing therapeutic target for treating this malignant disease.