Aberrant chromatin regulation can promote the initiation and progression of human cancer. An improved understanding of such mechanisms has resulted in the identification of cancers with an enhanced dependency on specific chromatin regulatory proteins relative to nonmalignant cell types. Hence, targeting of such complexes with small molecules has significant therapeutic potential in oncology. In recent years, several drugs have been developed and evaluated in human cancer patients, which can influence tumor biology by reprogramming of chromatin structure. In this review, we summarize several of the known mechanisms that endow cancer cells with a powerful dependency on chromatin regulation that exceeds the requirements for normal tissue homeostasis. We also summarize the remarkable small-molecule inhibitors that exploit chromatin regulator dependencies with a clear therapeutic benefit in human cancer patients.

C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences; and owns stock from Treeline Biosciences.

This work was supported by Cold Spring Harbor Laboratory NCI Cancer Center Support Grant CA045508. Additional funding was provided to C.R.V. by the Pershing Square Sohn Cancer Research Alliance, National Institutes of Health Grants CA013106, CA242919, CA174793, and CA229699. Y.G. is supported by the NCI award K99CA273523.

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