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PMID: 19608766 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The combined status of ATM and p53 link tumor development with therapeutic response.

Genes & development ·Vol. 23 ·No. 16 ·2009-08-15 ·Pages 1895-909

Jiang H, Reinhardt HC, Bartkova J, Tommiska J, Blomqvist C, Nevanlinna H, Bartek J, Yaffe MB, Hemann MT

Abstract

While the contribution of specific tumor suppressor networks to cancer development has been the subject of considerable recent study, it remains unclear how alterations in these networks are integrated to influence the response of tumors to anti-cancer treatments. Here, we show that mechanisms commonly used by tumors to bypass early neoplastic checkpoints ultimately determine chemotherapeutic response and generate tumor-specific vulnerabilities that can be exploited with targeted therapies. Specifically, evaluation of the combined status of ATM and p53, two commonly mutated tumor suppressor genes, can help to predict the clinical response to genotoxic chemotherapies. We show that in p53-deficient settings, suppression of ATM dramatically sensitizes tumors to DNA-damaging chemotherapy, whereas, conversely, in the presence of functional p53, suppression of ATM or its downstream target Chk2 actually protects tumors from being killed by genotoxic agents. Furthermore, ATM-deficient cancer cells display strong nononcogene addiction to DNA-PKcs for survival after DNA damage, such that suppression of DNA-PKcs in vivo resensitizes inherently chemoresistant ATM-deficient tumors to genotoxic chemotherapy. Thus, the specific set of alterations induced during tumor development plays a dominant role in determining both the tumor response to conventional chemotherapy and specific susceptibilities to targeted therapies in a given malignancy.

MeSH Terms
Animals Antineoplastic Agents/pharmacology,therapeutic use Apoptosis/drug effects Ataxia Telangiectasia Mutated Proteins Breast Neoplasms/drug therapy,physiopathology Cell Cycle Proteins/metabolism Cell Line, Tumor Checkpoint Kinase 2 DNA-Binding Proteins/deficiency,metabolism Drug Resistance, Neoplasm Female Humans Mice Mice, Nude NIH 3T3 Cells Neoplasms/drug therapy,physiopathology Protein Serine-Threonine Kinases/deficiency,metabolism Signal Transduction Survival Analysis Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins/deficiency,metabolism
Chemicals
Antineoplastic Agents Cell Cycle Proteins DNA-Binding Proteins Tumor Suppressor Protein p53 Tumor Suppressor Proteins XLF protein, mouse Checkpoint Kinase 2 ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse CHEK2 protein, human Chek2 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Jiang Hai
The Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Reinhardt H Christian
Bartkova Jirina
Tommiska Johanna
Blomqvist Carl
Nevanlinna Heli
Bartek Jiri
Yaffe Michael B
Hemann Michael T
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1815309
Published
2009-08-15
Epub
2009-00-16
Pages
1895-909
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2725944
Subset
IM
Grants
NIEHS NIH HHS · R01 ES015339 · United States
NIEHS NIH HHS · R01 ES15339 · United States
NCI NIH HHS · 1 R01 CA128803-01 · United States
NCI NIH HHS · R01 CA128803 · United States
NCI NIH HHS · U54 CA112967 · United States
External Links
PubMed source DOI: 10.1101/gad.1815309 PMC Full Text View journal details
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