Advances in Quantitative Systems Pharmacology Modeling of Synthetic Lethality Drug Research and Development: from Mechanism to Application

Synthetic lethality has emerged as a promising therapeutic strategy for precision targeting of tumor cells in cancer treatment. As it involves multiple DNA repair pathways, drug target research in this field has expanded from poly ADP-ribose polymerase (PARP) to many novel targets, with related therapies advancing progressively into pivotal clinical trials. Although synthetic lethality drugs can demonstrate significant and specific anticancer efficacy, their clinical development still faces such challenges as acquired resistance and hematological toxicity. To address these limitations, this review comprehensively summarizes the mechanisms of action of multiple targets in the synthetic lethality field and the research progress of quantitative systems pharmacology (QSP) models. QSP modeling, by integrating multi-scale mechanisms and experimental data, enables the prediction of clinical efficacy and hematological toxicity of synthetic lethality drugs. It plays a guiding role in clinical dosing regimen design, dose optimization, and combination therapy screening, thereby advancing the precise clinical translation of such drugs from a systems perspective, aiming to enhance patient clinical benefits and reduce safety risks.