Hierarchies of resistance to DNA damage response inhibitors: from pathway restoration to replication stress tolerance

: DNA damage response (DDR) inhibitors have reshaped precision oncology by exploiting tumor-specific vulnerabilities in genome maintenance and replication stress control. The clinical success of poly(ADP-ribose) polymerase (PARP) inhibitors-particularly in homologous recombination-deficient cancers-has validated this strategy, establishing a paradigmatic model for DDR-targeted therapies; however, both intrinsic and acquired resistance remain pervasive and limit durable benefit. In this Review, we analyze resistance mechanisms with a framework centered on PARP inhibitor biology, while extending key principles to other DDR-targeting strategies. We propose a hierarchical model that distinguishes dominant resistance drivers-mechanisms that restore DNA repair capacity or bypass the inhibited node (e.g., homologous recombination reactivation or checkpoint rewiring)-from adaptive resistance mechanisms that increase replication stress tolerance without restoring repair function, including replication-fork protection, metabolic reprogramming, cellular plasticity, and microenvironmental support. We discuss how tumor heterogeneity and therapy-imposed selective pressures shape clonal evolution and complicate biomarker development. We also critically evaluate combination strategies, highlighting why strong mechanistic rationale often fails to translate into consistent clinical benefit due to toxicity, scheduling constraints, and insufficient biomarker guidance. Finally, we outline priorities for moving beyond static genomic classifiers toward functional and longitudinal assessment of replication stress, DNA repair engagement, and tumor evolution to support more durable, biologically informed therapeutic strategies.