Exploring the Potential of Homologous Recombination Protein PALB2 in Synthetic Lethal Combinations

Cells with defective homologous recombination (HR) are highly sensitive to poly(ADP-ribose) polymerase (PARP) inhibition. Current therapeutic approaches leverage this vulnerability by using PARP inhibitors in cells with genetically compromised HR. However, if HR factors in cancer cells could be inhibited or degraded pharmacologically, it might reveal other opportunities for synergistic combinations. In this study, we developed a model system that recapitulates PARP/HR synthetic lethality by integrating a small-molecule responsive zinc-finger degron into the HR factor Partner and Localizer of BRCA2 (PALB2). We further tested a series of peptide ligands for PALB2 based on its natural binding partners, which led to the discovery of a high affinity peptide that will support future work on PALB2 and HR. Together, our findings validate PALB2 as a promising drug target and provide the tools and starting points for developing molecules with therapeutic applications.