Homoharringtonine targets XPC to inhibit DNA damage repair and sensitize tumors to platinum-based chemotherapy

DNA damage repair (DDR) is critical for maintaining genomic stability and serves as a promising target for cancer therapy development. Researchers have discovered that homoharringtonine (HHT), a drug previously used to treat leukemia, can inhibit DDR, offering a new way to boost the effectiveness of platinum-based chemotherapy.

Using a high-content screening method, scientists identified HHT as a novel DDR inhibitor. This drug binds tightly to XPC, a vital component of nucleotide excision repair (NER) that repairs damaged DNA. Specifically, HHT attaches to Thr795 of XPC with high affinity (Kd = 158.4 nM). By interfering with XPC's interaction with damaged DNA, HHT disrupts NER and decreases the efficiency of non-homologous end joining (NHEJ), a second DNA repair pathway.

As a result, HHT makes tumor cells more susceptible to platinum-based chemotherapy both in laboratory tests and animal models. This discovery demonstrates that a phenotype-driven screening approach can efficiently uncover potential DDR inhibitors. Furthermore, HHT emerges as a unique XPC inhibitor, opening up new possibilities for enhancing the effectiveness of platinum-based therapies in solid tumors.