Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models.

Abstract

Patients with triple-negative breast cancer (TNBC) - defined by lack of estrogen receptor and progesterone receptor expression as well as lack of human epidermal growth factor receptor 2 (HER2) amplification - have a poor prognosis. There is a need for targeted therapies to treat this condition. TNBCs frequently harbor mutations in TP53, resulting in loss of the G1 checkpoint and reliance on checkpoint kinase 1 (Chk1) to arrest cells in response to DNA damage. Previous studies have shown that inhibition of Chk1 in a p53-deficient background results in apoptosis [corrected] in response to DNA damage. We therefore tested whether inhibition of Chk1 could potentiate the cytotoxicity of the DNA damaging agent irinotecan in TNBC using xenotransplant tumor models. Tumor specimens from patients with TNBC were engrafted into humanized mammary fat pads of immunodeficient mice to create 3 independent human-in-mouse TNBC lines: 1 WT (WU-BC3) and 2 mutant for TP53 (WU-BC4 and WU-BC5). These lines were tested for their response to irinotecan and a Chk1 inhibitor (either UCN-01 or AZD7762), either as single agents or in combination. The combination therapy induced checkpoint bypass and apoptosis in WU-BC4 and WU-BC5, but not WU-BC3, tumors. Moreover, combination therapy inhibited tumor growth and prolonged survival of mice bearing the WU-BC4 line, but not the WU-BC3 line. In addition, knockdown of p53 sensitized WU-BC3 tumors to the combination therapy. These results demonstrate that p53 is a major determinant of how TNBCs respond to therapies that combine DNA damage with Chk1 inhibition.

• Authors: Cynthia X Ma, Shirong Cai, Shunqiang Li, Christine E Ryan, Zhanfang Guo, W Timothy Schaiff, Li Lin, Jeremy Hoog, Reece J Goiffon, Aleix Prat, Rebecca L Aft, Matthew J Ellis, Helen Piwnica-Worms
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 4 Pg. 1541-52 (Apr 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 22446188 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• DNA, Neoplasm
• Neoplasm Proteins
• Protein Kinase Inhibitors
• Receptors, Estrogen
• Receptors, Progesterone
• TP53 protein, human
• Thiophenes
• Tumor Suppressor Protein p53
• Irinotecan
• 7-hydroxystaurosporine
• Urea
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse
• Staurosporine
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Breast Neoplasms (chemistry, drug therapy)
• Camptothecin (administration & dosage, analogs & derivatives, therapeutic use)
• Cell Cycle (drug effects)
• Cell Line, Tumor (metabolism, transplantation)
• Checkpoint Kinase 1
• DNA Damage
• DNA, Neoplasm (drug effects)
• Female
• Genes, cdc
• Genes, erbB-2
• Genes, p53
• Humans
• Irinotecan
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Molecular Targeted Therapy
• Neoplasm Proteins (analysis, antagonists & inhibitors, physiology)
• Protein Kinase Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Protein Kinases (drug effects, physiology)
• Receptors, Estrogen (analysis, genetics)
• Receptors, Progesterone (analysis, genetics)
• Staurosporine (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Thiophenes (administration & dosage, pharmacology, therapeutic use)
• Tumor Suppressor Protein p53 (deficiency)
• Urea (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays