Systems biology reveals new atrategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab

Dana Faratian, Alexey Goltsov, Galina Lebedeva, Anatoly Sorokin, Stuart Moodie, Peter Mullen, Charlene Kay, In Hwa Um, Simon P. Langdon, Igor Goryanin, David J. Harrison

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Resistance to targeted cancer therapies such as trastuzumab is a frequent clinical problem not solely because of insufficient expression of HER2 receptor but also because of the overriding activation states of cell signaling pathways. Systems biology approaches lend themselves to rapid in silico testing of factors, which may confer resistance to targeted therapies. Inthis study, we aimed to develop a new kinetic model that could be interrogated to predict resistance to receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions in vitro and in clinical samples. The new mathematical model included RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition, AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of PTEN. The model was parameterized using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays. Quantitative PTEN protein expression was found to be the key determinant of resistance to anti-HER2 therapy in silico, which was predictive of unseen experiments in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative measurement is more predictive of response (relative risk, 3.0; 95% confidence interval, 1.6–5.5; P <0.0001) than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of 122 breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalized therapy in cancer and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision making in patients treated with anti-HER2 therapies.
Original languageEnglish
Pages (from-to)6713-6720
Number of pages8
JournalCancer Research
Volume69
Issue number16
DOIs
Publication statusPublished - 15 Aug 2009

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Precision Medicine
Systems Biology
Neoplasms
Receptor Protein-Tyrosine Kinases
Computer Simulation
Therapeutics
PTEN Phosphohydrolase
Cell Line
Protein Array Analysis
Phosphoproteins
Dimerization
Trastuzumab
Mitogen-Activated Protein Kinases
Theoretical Models
Multivariate Analysis
Confidence Intervals
Breast Neoplasms
Antibodies

Cite this

Faratian, D., Goltsov, A., Lebedeva, G., Sorokin, A., Moodie, S., Mullen, P., ... Harrison, D. J. (2009). Systems biology reveals new atrategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Research, 69(16), 6713-6720. https://doi.org/10.1158/0008-5472.CAN-09-0777
Faratian, Dana ; Goltsov, Alexey ; Lebedeva, Galina ; Sorokin, Anatoly ; Moodie, Stuart ; Mullen, Peter ; Kay, Charlene ; Um, In Hwa ; Langdon, Simon P. ; Goryanin, Igor ; Harrison, David J. / Systems biology reveals new atrategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. In: Cancer Research. 2009 ; Vol. 69, No. 16. pp. 6713-6720.
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Faratian, D, Goltsov, A, Lebedeva, G, Sorokin, A, Moodie, S, Mullen, P, Kay, C, Um, IH, Langdon, SP, Goryanin, I & Harrison, DJ 2009, 'Systems biology reveals new atrategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab', Cancer Research, vol. 69, no. 16, pp. 6713-6720. https://doi.org/10.1158/0008-5472.CAN-09-0777

Systems biology reveals new atrategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. / Faratian, Dana; Goltsov, Alexey; Lebedeva, Galina; Sorokin, Anatoly; Moodie, Stuart; Mullen, Peter; Kay, Charlene; Um, In Hwa; Langdon, Simon P.; Goryanin, Igor; Harrison, David J.

In: Cancer Research, Vol. 69, No. 16, 15.08.2009, p. 6713-6720.

Research output: Contribution to journalArticle

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AU - Faratian, Dana

AU - Goltsov, Alexey

AU - Lebedeva, Galina

AU - Sorokin, Anatoly

AU - Moodie, Stuart

AU - Mullen, Peter

AU - Kay, Charlene

AU - Um, In Hwa

AU - Langdon, Simon P.

AU - Goryanin, Igor

AU - Harrison, David J.

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