Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells.

Abstract

Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras-MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify cancer patients that may benefit from Chk1-targeted therapy. Mol Cancer Ther; 16(4); 694-704. ©2017 AACR.

• Authors: Ho-June Lee, Yi Cao, Victoria Pham, Elizabeth Blackwood, Catherine Wilson, Marie Evangelista, Christiaan Klijn, David Stokoe, Jeff Settleman
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 16 Issue 4 Pg. 694-704 (04 2017) ISSN: 1538-8514 [Electronic] United States
• PMID: 28138032 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Heterocyclic Compounds, 3-Ring
• Piperidines
• Deoxycytidine
• GDC-0425
• CHEK1 protein, human
• Checkpoint Kinase 1
• Proto-Oncogene Proteins p21(ras)
• Gemcitabine

Topics

• Animals
• Bone Neoplasms (drug therapy, genetics)
• Breast Neoplasms (genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Checkpoint Kinase 1 (genetics)
• DNA Damage
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacology)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Heterocyclic Compounds, 3-Ring (administration & dosage, therapeutic use)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Osteosarcoma (drug therapy, genetics)
• Ovarian Neoplasms (genetics)
• Piperidines (administration & dosage, therapeutic use)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Xenograft Model Antitumor Assays
• Gemcitabine