Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells.

Abstract

Breast cancer is the second leading cause of cancer-related death among women. Here we report a role for the protein kinase p38α in coordinating the DNA damage response and limiting chromosome instability during breast tumor progression, and identify the DNA repair regulator CtIP as a p38α substrate. Accordingly, decreased p38α signaling results in impaired ATR activation and homologous recombination repair, with concomitant increases in replication stress, DNA damage, and chromosome instability, leading to cancer cell death and tumor regression. Moreover, we show that pharmacological inhibition of p38α potentiates the effects of taxanes by boosting chromosome instability in murine models and patient-derived xenografts, suggesting the potential interest of combining p38α inhibitors with chemotherapeutic drugs that induce chromosome instability.

• Authors: Begoña Cánovas, Ana Igea, Alessandro A Sartori, Roger R Gomis, Tanya T Paull, Michitaka Isoda, Héctor Pérez-Montoyo, Violeta Serra, Eva González-Suárez, Travis H Stracker, Angel R Nebreda
• Journal: Cancer cell (Cancer Cell) Vol. 33 Issue 6 Pg. 1094-1110.e8 (06 11 2018) ISSN: 1878-3686 [Electronic] United States
• PMID: 29805078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Benzamides
• PH 797804
• Pyridones
• Taxoids
• Mitogen-Activated Protein Kinase 14

Topics

• Animals
• Benzamides (pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Chromosomal Instability (drug effects)
• DNA Damage
• Disease Progression
• Female
• Humans
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 14 (antagonists & inhibitors, genetics, metabolism)
• Molecular Targeted Therapy
• Pyridones (pharmacology)
• Recombinational DNA Repair (drug effects, genetics)
• Taxoids (pharmacology)
• Xenograft Model Antitumor Assays