H3K36me3-Deficient Cancers Are Sensitive to WEE1 Kinase Inhibition

Loss of histone H3 trimethylation at lysine 36 (H3K36me3) is frequently observed in tumors and is associated with a poor outcome. H3K36me3 loss can occur via multiple mechanisms, including loss of the tumor suppressor methyltransferase SET domain–containing 2 (SETD2). However, there are currently no therapies to specifically target H3K36me3-deficient cancers. Pfister and colleagues found that H3K36me3-deficient cancer cell lines were sensitive to treatment with AZD1775, an inhibitor of WEE1 kinase, which suppresses cyclin-dependent kinases 1 (CDK1) and CDK2. Depletion of SETD2 in wild-type cells sensitized them to AZD1775 treatment, confirming a synthetic lethal interaction between H3K36me3 loss and WEE1 inhibition in human cells. This selective killing of H3K36me3-deficient cells resulted from inhibition of DNA replication, with SETD2 loss leading to fork stalling and WEE1 inhibition causing stalled fork collapse. Expression of the RRM2 subunit of ribonucleotide reductase, which generates dNTPs for DNA synthesis, was reduced by AZD1775 treatment and SETD2 knockdown. Mechanistically, H3K36me3 loss decreased the transcription of RRM2 via impaired recruitment of transcription initiation factors, whereas WEE1 inhibition triggered unchecked CDK1/2 activity that enhanced aberrant origin firing and promoted CDK-dependent phosphorylation and ubiquitin-mediated degradation of RRM2, resulting in dNTP starvation and cell death. Consistent with this mechanism, overexpression of exogenous RRM2 rescued cells from death. WEE1 inhibition was effective in vivo and induced regression of SETD2-deficient, but not SETD2-proficient, tumor xenografts. Furthermore, a monoclonal antibody against H3K36me3 distinguished SETD2-deficient from SETD2-proficient tumors, suggesting that it may be possible to determine which patients might benefit from WEE1 inhibitors based on H3K36me3 immunohistochemistry. These findings indicate that WEE1 inhibition selectively kills H3K36me3-deficient cancer cells through RRM2 depletion and dNTP starvation, and suggest that WEE1 inhibition may be a promising strategy for treating H3K36me3-deficient tumors. As AZD1775 is already in clinical trials, these results have the potential to be rapidly translated to patient care.

Pfister SX, Markkanen E, Jiang Y, Sarkar S, Woodcock M, Orlando G, et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 2015;28:557–68.

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