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

Homoharringtonine (HHT) inhibits DNA damage repair by directly binding XPC, disrupting XPC–damaged DNA interaction with Kd = 158.4 nM and sensitizing tumors to platinum therapy.

• Why it matters: DDR both maintains genomic stability and limits the effectiveness of DNA-damaging chemotherapy, creating a need for DDR inhibitors that can sensitize cancer cells to platinum drugs.
• What they did: Using a phenotype-driven high-content screen for 53BP1 Tudor-domain foci formation, the study validated HHT as a DDR inhibitor and showed XPC binding dependent on Thr795, impairing NER and reducing NHEJ efficiency.
• The result: HHT sensitized tumor cells to platinum-based chemotherapy in vitro and in vivo, supporting a first-in-class XPC inhibition mechanism and enabling DDR inhibitor discovery via the 53BP1 foci platform.

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