Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer

// Shuying Liu 1 , Xiaolong Meng 1 , Huiqin Chen 1 , Wenbin Liu 2 , Todd Miller 3,4 , Mandi Murph 5 , Yiling Lu 6 , Fan Zhang 6 , Mihai Gagea 7 , Carlos L. Arteaga 4,8,9 ,Gordon B. Mills 6 , Funda Meric-Bernstam 10 and Ana M. González-Angulo 1,6 1 Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 2 Department of B ioinformatics and Computational Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 3 Department of Pharmacology & Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 4 Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 5 University of Georgia College of Pharmacy, Athens, GA 6 Department of S ystems Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 7 Department of V eterinary Medicine and Surgery, The University of Texas, MD Anderson Cancer Center, Houston, TX 8 Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 9 Department of M edicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 10 Department of S urgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX Correspondence: Ana Maria Gonzalez-Angulo, email: // Keywords : breast cancer, targeting therapy, dasatinib, fulvestrant, MK0646 Received : April 15, 2014 Accepted : May 26, 2014 Published : May 27, 2014 Abstract Despite numerous therapies that effectively inhibit estrogen signaling in breast cancer, a significant proportion of patients with estrogen receptor (ER)-positive malignancy will succumb to their disease. Herein we demonstrate that long-term estrogen deprivation (LTED) therapy among ER-positive breast cancer cells results in the adaptive increase in ER expression and subsequent activation of multiple tyrosine kinases. Combination therapy with the ER down-regulator fulvestrant and dasatinib, a broad kinase inhibitor, exhibits synergistic activity against LTED cells, by reduction of cell proliferation, cell survival, cell invasion and mammary acinar formation. Screening kinase phosphorylation using protein arrays and functional proteomic analysis demonstrates that the combination of fulvestrant and dasatinib inhibits multiple tyrosine kinases and cancer-related pathways that are constitutively activated in LTED cells. Because LTED cells display increased insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF-1R) signaling, we added an ant-IGF-1 antibody to the combination with fulvestrant and dasatinib in an effort to further increase the inhibition. However, adding MK0646 only modestly increased the inhibition of cell growth in monolayer culture, but neither suppressed acinar formation nor inhibited cell migration in vitro and invasion in vivo. Therefore, combinations of fulvestrant and dasatinib, but not MK0646, may benefit patients with tyrosine-kinase-activated, endocrine therapy-resistant breast cancer.