Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation

Area of Science:

• Cancer Biology
• Epigenetics
• Molecular Oncology

Background:

• Histone H3K36 trimethylation (H3K36me3) loss is common in various cancers, presenting a potential therapeutic target.
• Understanding the molecular mechanisms driving cancer progression and identifying novel vulnerabilities is crucial for developing effective treatments.

Purpose of the Study:

• To identify synthetic lethal interactions in cancers with H3K36me3 deficiency.
• To elucidate the role of WEE1 inhibition and RRM2 in this synthetic lethality.
• To evaluate the therapeutic potential of WEE1 inhibitors in preclinical cancer models.

Main Methods:

• Investigated the synthetic lethal interaction between H3K36me3 deficiency and WEE1 inhibition.
• Utilized molecular biology techniques to study RRM2 regulation by H3K36me3 and WEE1.
• Assessed the impact of WEE1 inhibition on RRM2 levels, dNTP pools, cell cycle progression, and apoptosis.
• Tested the efficacy of WEE1 inhibitor AZD1775 in H3K36me3-deficient tumor xenografts.

Main Results:

• H3K36me3-deficient cancers exhibit acute sensitivity to WEE1 inhibition.
• WEE1 inhibition leads to RRM2 degradation via premature CDK activation, causing dNTP depletion and S-phase arrest.
• This synthetic lethality is dependent on RRM2 levels and can be rescued by increasing RRM2 expression or inhibiting its degradation.
• WEE1 inhibitor AZD1775 demonstrated tumor regression in H3K36me3-deficient xenografts.

Conclusions:

• WEE1 inhibition represents a promising synthetic lethal strategy for treating H3K36me3-deficient cancers.
• Targeting RRM2 degradation through WEE1 inhibition offers a novel therapeutic approach.
• AZD1775 shows preclinical efficacy, supporting its clinical investigation for relevant cancer types.