Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer

Summary

Principal Investigator: Naoto T Ueno
Affiliation: The University of Texas
Country: USA
Abstract: The epidermal growth factor receptor (EGFR) signaling pathway is a central regulator of cell growth and proliferation and modulates critical cell cycle regulatory molecules. This pathway has emerged as a promising target for cancer therapy. EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva) and gefitinib (Iressa), are approved for cancer treatment but have induced a clinical response in only a subgroup of patients. Therefore, EGFR-TKI's molecular mechanism of action needs to be better understood. My long-term goal is to elucidate the molecular mechanism of action of EGFR-TKI so that novel therapeutic approaches or diagnostic tools that are clinically relevant can be developed. I have recently shown that in vitro erlotinib sensitivity is partially dependent on the activity of cyclin-dependent kinase 2 (Cdk2), which is the most downstream kinase of the EGFR pathway that regulates the transition from the G1 phase to the S phase. The objective of this application is to determine which downstream molecules of the EGFR and non-EGFR signaling pathway predict the response to EGFR-TKIs. The central hypothesis of this proposal is that the effect of Cdk2 activity on EGFR-TKI-mediated cytotoxicity is regulated by downstream molecules of the cell signaling pathway, specifically ERK, p27, and PEA15. This hypothesis is based on the following observations. First, erlotinib inhibits the tyrosine kinase of EGFR in both erlotinib-sensitive and erlotinib-resistant breast cancer cells; however, erlotinib inhibits Cdk2 activity only in sensitive cells. These findings indicate that there is an abnormality in the EGFR signaling pathway in erlotinib-resistant cells. Second, phosphorylated ERK is downregulated and p27 is upregulated in erlotinib-sensitive cells, and the phosphorylation status of p27 affects its nuclear-cytoplasmic localization and expression level. Third, PEA15 sequesters ERK into the cytoplasm from the nucleus and reduces cell proliferation. I have designed three independent but interrelated specific aims to provide a comprehensive assessment of the downstream EGFR and non-EGFR signaling pathway in breast cancer cells treated with EGFR-TKI. Specific Aim 1. Establish how erlotinib regulates p27 to suppress Cdk2 activity in vitro. Specific Aim 2. Establish how PEA15 modulates erlotinib sensitivity in vitro and in vivo. Specific Aim 3. Establish in vivo biomarkers that predict erlotinib sensitivity. Relevance: This study will provide significant insight into the role of downstream molecules affected by EGFR-TKI. Our findings will improve the outcome of cancer patients by increasing EGFR-TKI efficacy and facilitating the selection of patients who may benefit from EGFR-TKI therapy.
Funding Period: 2007-07-05 - 2012-05-31
more information: NIH RePORT

Top Publications

  1. pmc A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression
    Jangsoon Lee
    Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
    Breast Cancer Res Treat 146:259-72. 2014
  2. doi TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase
    Xiaoping Wang
    Authors Affiliations Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Departments of Molecular and Cellular Oncology, Pathology, Radiation Oncology, and Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas Tolero Pharmaceuticals, Inc, Salt Lake City, Utah and Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
    Cancer Res 73:6516-25. 2013
  3. pmc Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes
    Hiroko Masuda
    Authors Affiliations Morgan Welch Inflammatory Breast Cancer Research Program and Clinic Departments of Breast Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas and Department of Biochemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
    Clin Cancer Res 19:5533-40. 2013
  4. pmc Statin use in primary inflammatory breast cancer: a cohort study
    T M Brewer
    Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Br J Cancer 109:318-24. 2013
  5. pmc Genomic and expression analysis of microdissected inflammatory breast cancer
    Wendy A Woodward
    Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    Breast Cancer Res Treat 138:761-72. 2013
  6. pmc Ink4a/Arf(-/-) and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f(-) quiescent cells
    K Kai
    1 Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
    Oncogene 33:440-8. 2014
  7. pmc Adding hormonal therapy to chemotherapy and trastuzumab improves prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor 2-positive primary breast cancer
    Naoki Hayashi
    Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Breast Cancer Res Treat 137:523-31. 2013
  8. pmc Role of epidermal growth factor receptor in breast cancer
    Hiroko Masuda
    Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Breast Cancer Res Treat 136:331-45. 2012
  9. pmc Inflammatory breast cancer: what we know and what we need to learn
    Hideko Yamauchi
    Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncologist 17:891-9. 2012
  10. pmc Gemcitabine Overcomes Erlotinib Resistance in EGFR-Overexpressing Cancer Cells through Downregulation of Akt
    Chandra Bartholomeusz
    1 Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas
    J Cancer 2:435-42. 2011

Detail Information

Publications19

  1. pmc A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression
    Jangsoon Lee
    Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
    Breast Cancer Res Treat 146:259-72. 2014
    ..Our finding justifies for conducting a clinical trial of combinational treatment with entinostat, lapatinib, and trastuzumab in patients with HER2-overexpressing breast cancer resistant to trastuzumab-based treatment...
  2. doi TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase
    Xiaoping Wang
    Authors Affiliations Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Departments of Molecular and Cellular Oncology, Pathology, Radiation Oncology, and Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas Tolero Pharmaceuticals, Inc, Salt Lake City, Utah and Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
    Cancer Res 73:6516-25. 2013
    ..Our findings establish that TIG1 positively modifies the malignant properties of IBC by supporting Axl function, advancing understanding of its development and rationalizing TIG1 and Axl as promising therapeutic targets in IBC treatment...
  3. pmc Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes
    Hiroko Masuda
    Authors Affiliations Morgan Welch Inflammatory Breast Cancer Research Program and Clinic Departments of Breast Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas and Department of Biochemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
    Clin Cancer Res 19:5533-40. 2013
    ..We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes...
  4. pmc Statin use in primary inflammatory breast cancer: a cohort study
    T M Brewer
    Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Br J Cancer 109:318-24. 2013
    ..Some studies have suggested that statins, which have cholesterol-lowering and anti-inflammatory properties, may have antitumor effects. Effects of statins on inflammatory breast cancer (IBC) have never been studied...
  5. pmc Genomic and expression analysis of microdissected inflammatory breast cancer
    Wendy A Woodward
    Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    Breast Cancer Res Treat 138:761-72. 2013
    ..Inflammatory breast cancer comparative genomic hybridization data are presented, but a validated genomic data set that identifies IBC is not demonstrated...
  6. pmc Ink4a/Arf(-/-) and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f(-) quiescent cells
    K Kai
    1 Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
    Oncogene 33:440-8. 2014
    ..Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human TNBC. ..
  7. pmc Adding hormonal therapy to chemotherapy and trastuzumab improves prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor 2-positive primary breast cancer
    Naoki Hayashi
    Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Breast Cancer Res Treat 137:523-31. 2013
    ..Adjuvant treatment without hormonal therapy is inferior for this patient population...
  8. pmc Role of epidermal growth factor receptor in breast cancer
    Hiroko Masuda
    Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Breast Cancer Res Treat 136:331-45. 2012
    ..Further studies of the role of EGFR in TNBC and IBC are needed to better understand the best way to use EGFR-targeted therapy-e.g., as a chemosensitizer or to prevent metastases-to treat these aggressive diseases...
  9. pmc Inflammatory breast cancer: what we know and what we need to learn
    Hideko Yamauchi
    Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncologist 17:891-9. 2012
    ..We review the current status of multidisciplinary care for patients with inflammatory breast cancer (IBC) and discuss what further research is needed to advance the care of patients with this disease...
  10. pmc Gemcitabine Overcomes Erlotinib Resistance in EGFR-Overexpressing Cancer Cells through Downregulation of Akt
    Chandra Bartholomeusz
    1 Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas
    J Cancer 2:435-42. 2011
    ..Our data show that gemcitabine increased the cytotoxic effect of erlotinib by downregulating p-Akt in EGFR-overexpressing cells with either intrinsic or acquired erlotinib resistance...
  11. pmc Targeting EGFR in Triple Negative Breast Cancer
    Naoto T Ueno
    1 Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    J Cancer 2:324-8. 2011
    ....
  12. pmc Prognostic impact of phosphorylated HER-2 in HER-2+ primary breast cancer
    Naoki Hayashi
    Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Oncologist 16:956-65. 2011
    ..We determined the prognostic value of the expression level of tyrosine 1248-phosphorylated HER-2 (pHER-2) in patients with HER-2(+) primary breast cancer using a reverse-phase protein array...
  13. pmc Different gene expressions are associated with the different molecular subtypes of inflammatory breast cancer
    Takayuki Iwamoto
    Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Breast Cancer Res Treat 125:785-95. 2011
    ..IBC tumors can be divided into molecular and clinical subtypes similar to those of non-IBC. Clinical subtypes of IBC show molecular differences compared with similar subtypes of non-IBC...
  14. pmc Silencing kinase-interacting stathmin gene enhances erlotinib sensitivity by inhibiting Ser¹⁰ p27 phosphorylation in epidermal growth factor receptor-expressing breast cancer
    Dongwei Zhang
    Breast Cancer Translational Research Laboratory, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cancer Ther 9:3090-9. 2010
    ..Our study provides a rationale for the development of combinations of erlotinib with KIS inhibition to overcome EGFR TKI resistance in EGFR-expressing breast cancer...
  15. ncbi Targeted therapy in inflammatory breast cancer
    Hideko Yamauchi
    Department of Breast Surgical Oncology, St Luke s International Hospital, Tokyo, Japan
    Cancer 116:2758-9. 2010
    ..On the basis of dissecting the molecular mechanism of the aggressiveness of IBC, the authors currently are investigating whether EGFR may aid in developing innovative targeted therapies...
  16. pmc Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer
    Dongwei Zhang
    Breast Cancer Translational Research Laboratory, Department of Breast Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Clin Cancer Res 15:6639-48. 2009
    ..Epidermal growth factor receptor (EGFR) expression is an independent poor prognostic factor in IBC. The purpose of this study was to determine the effect on IBC tumorigenicity and metastasis of blocking the EGFR pathway...
  17. pmc Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells
    Dongwei Zhang
    Department of Breast Medical Oncology, Unit 1354, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Mol Cancer Ther 7:1846-50. 2008
    ..We conclude that the in vitro activity of lapatinib is not dependent on EGFR expression level in HER2-overexpressing breast cancer cells...
  18. ncbi Quantitative magnetic resonance spectroscopy reveals a potential relationship between radiation-induced changes in rat brain metabolites and cognitive impairment
    Todd Atwood
    Department of Radiation Oncology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    Radiat Res 168:574-81. 2007
    ....
  19. pmc Sensitivity of breast cancer cells to erlotinib depends on cyclin-dependent kinase 2 activity
    Fumiyuki Yamasaki
    Breast Cancer Translational Research Laboratory, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77030 4009, USA
    Mol Cancer Ther 6:2168-77. 2007
    ....