Targeted protein degradation has emerged as a promising tool in anticancer therapy, primarily aimed at degrading oncogenic drivers.

Here, we suggest the use of PROTACs that rely on E3 ligases defective in cancer cells to selectively protect normal, healthy tissues from the dose-limiting toxicity of drugs used in cancer treatment. We have named this approach PROTAC-Driven Protective Therapy (PDPT). PDPT treatment combines a given anticancer compound with a PROTAC that degrades proteins required for the drug-induced toxicity. Drug uptake transporters, pro-drug activating enzymes, and the actual drug target in cases that mediate the drug-induced toxicity are all examples of potential targets for protective PROTACs. Importantly, these protective PROTACs must recruit E3 ligases that are mutated or defective in the cancer cells while remaining functional in healthy tissues.

As proof of concept of our strategy, we demonstrate that PARP1 degradation by CRBN-recruiting or VHL-recruiting PROTACs alleviates the cytotoxicity of PARP inhibitors (PARPi) in E3 ligase-proficient cells, while E3 ligase-deficient cancer cells remain fully sensitive. Notably, PDPT also protects primary human bone marrow progenitors, which are the most clinically relevant cells affected by PARPi-associated side effects in cancer patients, from PARPi-induced toxicity. These results support the potential clinical relevance of the PDPT strategy. Furthermore, we uncover that MDM2-recruiting PROTACs are inefficient in TP53-mutant cancers. This tumor-intrinsic property enables the potential application of PDPT in TP53-mutant cancers utilizing MDM2-recruiting PROTACs.

PDPT proposes a novel application for targeted protein degradation with the potential to improve tolerability and expand the therapeutic window of both established and forthcoming cancer therapies.

We thank Dr. Cristina Mayor for providing advice and sharing reagents. This work was supported by grants from the Scientific Foundation of the Spanish Association Against Cancer (PRYGN259366LOPE), the Spanish Ministry of Science and Innovation-Agencia Estatal de Investigacion (PID2020-119329RB-I00 and PID2024-161099OB-I00). L.S.-C. was supported with a postdoctoral grant from the Scientific Foundation of the Spanish Association Against Cancer (POSTD211274SIMO). M.L.-P. was supported by the FPU22-00250 and S.R. by the FPU23-00552 fellowships from the Spanish Ministry of Science, Innovation and Universities. E.P. was supported by the by the HORIZON-MSCA ITN RepliFate (101072903).