C. Kent Osborne, M.D.
Medicine and Molecular and Cellular Biology
Lester and Sue Smith Breast Center
Dan L. Duncan Cancer Center at Baylor College of Medicine
MD: University of Missouri Medical School
Postdoctoral training: National Cancer Institute, NIH
Mechanism of Resistance to ER and HER2-targeted Therapies
Therapies targeting ER and HER2 have been very effective in the treatment of breast cancer resulting in striking reductions in recurrence and improvements in survival from the disease. Still some patients have de novo or develop acquired resistance to these therapies which then results in tumor recurrence and death. Our laboratory is interested in understanding the driver pathways as well as escape mechanisms activated when the primary driver is blocked to cause resistance, in order to design better treatment strategies. Using in vitro and in vivo preclinical models as well as tumor samples from patients our goal is to first understand the mechanisms of resistance and then to translate those discoveries to the clinic for improved patient outcome. We have found that one mechanism of resistance is related to the extensive crosstalk between the ER and HER signaling pathways. As a consequence, increased ER signaling accounts for resistance in some patients to HER-targeted therapy, while increased HER signaling can cause resistance to ER-targeted therapy. Other pathways such as the beta integrin pathway, the PI3K/AKT pathway and stress kinase pathways can also function as escape pathways thereby contributing to resistance to initial treatment. We have also shown that complete blockade of the driver pathway is necessary for optimal treatment. The most notable example is the HER pathway where we showed first in preclinical models that inhibition of signaling from all homo-and heterodimer receptor pairs of HER1, 2, and 3 using multiple drugs is necessary for optimal therapy. This hypothesis was recently confirmed in patients in a neoadjuvant clinical trial where combined inhibitors of HER signaling were capable of eradicating cancer from the breast. Now using a variety of genomic, transcriptomic, epigenomic, and proteomic platforms, we are discovering other mechanisms of resistance using both preclinical cell lines and samples from patients treated with HER and ER-targeting agents.
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
- A C Chen., I Migliaccio, M Rimawi, S Lopez-Tarruella, C J Creighton, S Massarrweh, C Huang, Y-C Wang, S K Batra, M CGutierrez, C K Osborne, R Schiff. Upregulation of Mucin4 in ER+/HER2-overexpressing xenografts with acquired resistance to endocrine and HER2-targeted therapies. (March 2012) Submitted to Breast Cancer Res & Treatment. PMID:22644656
- M Rimawi, C K Osborne. Blocking both driver and escape pathways improves outcomes. (2012) Nature Reviews 9:133-134.
- C L Arteaga, M X Sliwkowski, C K Osborne, E A Perez, F Puglisi, L Gianni. Treatment of HER2-positive breast cancer: current status and future perspectives. (2011) Nat Rev Clin Oncol. 9(1):16-32. PMID:22124364
- Y-C Wang, G Morrison, R Gillihan, J Guo, R M Ward, X Fu, M F Botero, N A Healy, S G Hilsenbeck, G L Phillips, G C Chamness, M F Rimawi, C K Osborne, R Schiff. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers – role of estrogen receptor and HER2 reactivation. (2011) Breast Cancer Res. Nov 28;13(6):R121. PMID: 22123186
- T Sun, N Aceto, K L Meerbrey, J D Kessler, C Zhou, I Migliaccio, D X Nguyen, N N Ravlova, M Botero J Huang, R J Bernardi, E Schmitt, G Hu, M Z Li, N Dephoure, S P Gygi, M Rao, C J Creighton, S G Hilsenbeck, C A Shaw, D Muzny, R A Gibbs, D A Wheeler, C K Osborne, R Schiff, M Berntires-Aljj, S J Elledge, T F Westbrook. Activation of Multiple Prot-oncogenic Tyrosine Kinases in Breast Cancer via Loss of the PTPN12 Phosphatase. (2011) Cell 144:703-718.
- M F Rimawi, Y-C Wang, C Huang, I Migliaccio, M C Gutierrez, J Wu, S G Hilsenbeck, G Arpino, S Massarweh, R Ward, R Soliz, C K Osborne, R Schiff. Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway as a therapeutic strategy in HER-2/neu (ErbB-2) overexpressing breast tumor xenografts. (2011) Clin Can Res 17:1351-1361. PMID:21138857 PMC3060302
- C K Osborne, and R Schiff. Mechanisms of endocrine resistance in breast cancer. (2011) Annual Review of Medicine. Vol 62(1). PMID20887199
- B Dave, I Migliaccio, M C Gutierrez, M-F Wu, G C Chamness, H Wong, A Narasanna, A Chakrabarty, S G Hilsenbeck, J Huang, M Rimawi, R Schiff, C Artega, C KOsborne. C Chang. Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2-Overexpressing Locally Advanced Breast Cancers. (2010) JCO 29:66-173. PMID21135276 PMC3058274
- C Huang, C C Park, S G Hilsenbeck, R Ward, M F Rimawi, Y-C Wang, J Shou, M J Bissell, C K Osborne, R Schiff. β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. (2011) Breast Cancer Res 13(4):R84. PMID: 21883473
- C K Osborne, P Neven, L Dirix, J Mackey, J Robert, C Underhill, R Schiff, C Gutierrez, P Magill, M Seller. Gefitinib or Placebo in Combination with Tamoxifen in Patients with ER/PgR-Positive Metastatic Breast Cancer: a Randomized Phase II Study. (2011) Clin Cancer Res 17(5):1147-1159. PMID 21220480 PMC3074404