Abstract
Inhibiting p38α blocks DNA repair by HR and increases CIN to suppress tumor progression.
Major finding: Inhibiting p38α blocks DNA repair by HR and increases CIN to suppress tumor progression.
Mechanism: p38α phosphorylates CtIP to promote DNA double strand break resection and repair.
Impact: Breast tumors with high levels of CIN may benefit from treatment with p38α inhibitors plus taxanes.
Chromosomal instability (CIN) can be induced by defects in DNA repair and increased DNA replication stress, but the effects of CIN on tumor progression are context dependent. Cánovas, Igea, and colleagues investigated the role of p38α, a ubiquitously expressed kinase involved in mediating the stress response to replication defects and DNA damage, in breast cancer cell survival and CIN. In a mouse model of breast cancer, p38α was required for tumor progression, and deletion of Mapk14 (encoding p38α) resulted in tumor regression with increased levels of DNA damage. In vitro, p38α was required to prevent cell death and maintain efficient cell-cycle progression in mammary tumor epithelial cells. p38α directly phosphorylated CtIP, which is involved in DNA double strand break (DSB) resection. Thus, deletion of p38α reduced ATR activation and suppressed DNA repair by homologous recombination (HR), resulting in an increase in replication stress, DNA damage, and CIN. Further, depletion of p38α sensitized cells to treatment with paclitaxel or docetaxel, taxane drugs that trigger missegregation in proliferating cells to promote CIN. Consistent with these findings, treatment with the p38α inhibitor PH797804 plus paclitaxel or docetaxel suppressed tumor growth in an autochthonous mouse model of breast cancer, whereas single-agent taxane treatment had only a cytostatic effect. Moreover, combined treatment was associated with increased DNA damage and missegregation events, suggesting that p38α contributes to the DNA damage response and promotes the survival of cancer cells with high levels of CIN. p38α inhibition also enhanced CIN and reduced tumor growth in combination with taxane treatment in breast cancer patient-derived xenograft models. In addition to elucidating a role for p38α in limiting replication stress and CIN, these findings suggest that tumors with high levels of aneuploidy may benefit from combination therapy with p38α inhibitors plus taxanes.
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