PROTAC-Driven Protective Therapy increases the therapeutic window of anticancer drugs

Targeted protein degradation is emerging as a powerful anticancer therapy, mostly focused on eliminating oncogenic drivers. In contrast, we propose using PROTACs that exploit E3 ligase defects in cancer cells to selectively protect healthy tissues from the dose-limiting toxicity of anticancer drugs. We term this approach PROTAC-Driven Protective Therapy (PDPT). PDPT consists of a combinatorial treatment of a given anticancer compound with a PROTAC that promotes the degradation of proteins required for the drug-induced toxicity. Potential targets of protective PROTACs include drug uptake transporters, enzymes activating pro-drugs, and the actual drug target in cases that mediates the drug-induced toxicity. Notably, these protective PROTACs must be designed to recruit E3 ligases that are mutated or defective in the cancer cells while remain active in healthy tissues. As a proof of concept of our strategy, we used CRBN-recruiting and VHL-recruiting PROTACs to demonstrate that PARP1 degradation alleviates the cytotoxicity of PARP inhibitors (PARPi) in E3 ligase-proficient cells, while E3 ligase-deficient cancer cells remain fully sensitive. Remarkably, PDPT also protects primary human bone marrow progenitors from PARPi-induced toxicity, which are the most clinically relevant cells affected by PARPi-associated side effects in cancer patients, supporting the clinical relevance of this strategy. We further uncover that TP53-mutant cancers display critically low expression of the E3 ligase MDM2 and show inefficient MDM2-recruiting PROTAC activity. This tumor-intrinsic feature enables PDPT using MDM2-recruiting PROTACs in TP53-mutant cancers. PDPT opens a new direction for targeted protein degradation by improving tolerability and expanding the therapeutic window of both established and future cancer therapies.