Thermal Proteome Profiling Reveals Insight to Antiproliferative and Pro‐Apoptotic Effects of Lagunamide A in the Modulation of DNA Damage Repair

Lagunamide A is a biologically active natural product with a yet unidentified molecular mode of action. Cellular studies revealed that lagunamide A is a potent inhibitor of cancer cell proliferation, promotes apoptosis and causes mitochondrial dysfunction. To decipher the cellular mechanism responsible for these effects, we utilized thermal protein profiling (TPP) and identified EYA3 as a stabilized protein in cells upon lagunamide A treatment. EYA3, involved in the DNA damage repair process, was functionally investigated via siRNA based knockdown studies and corresponding effects of lagunamide A on DNA repair were confirmed. Furthermore, we showed that lagunamide A sensitized tumor cells to treatment with the drug doxorubicin highlighting a putative therapeutic strategy. Using TPP (Thermal Proteome Profiling) we identify EYA3 as component of the molecular mode of action of the natural compound Lagunamide A (Lag A). Lag A targeting the DNA damage repair process sets a promising starting point to study basic chemotherapy resistance mechanisms and to develop more effective chemo‐sensitizing drugs.