PKMYT1 in Cancer: Beyond Cell Cycle Checkpoints to Context-Dependent Therapeutic Vulnerability

PKMYT1 has emerged as a promising therapeutic target distinguished by its tumor-selective expression and essential role in replication stress management. Unlike WEE1, PKMYT1 is dispensable in normal cell cycles but critical for cancer cells coping with DNA damage, establishing a broad therapeutic window. This vulnerability is exemplified by synthetic lethality in CCNE1-amplified and TP53-deficient contexts, where PKMYT1 inhibition triggers catastrophic mitotic entry. Beyond canonical cell cycle regulation, PKMYT1 functions as a multifaceted oncoprotein modulating signaling networks, metabolic reprogramming, and immune evasion via cGAS-STING activation. With selective inhibitors like lunresertib (RP-6306) now in Phase I/II trials, often combined with ATR inhibitors or chemotherapy, the field stands at a translational inflection point. However, context-dependent roles (e.g., tumor-suppressive functions in LUAD) and undefined resistance mechanisms pose challenges. This review critically evaluates PKMYT1's mechanistic underpinnings, clinical landscape, and biomarker strategies. We advocate for precision targeting based on genetic signatures (CCNE1, TP53, ER) to optimize therapeutic efficacy and overcome resistance in replication stress-high malignancies.