Combined Src and Aromatase Inhibition Impairs Human Breast Cancer Growth In vivo and Bypass Pathways Are Activated in AZD0530-Resistant Tumors

• Published in: Clinical cancer research 2009-05, Vol.15 (10), p.3396-3405
• Main Authors: YI CHEN, GUGGISBERG, Natalia, JORDA, Merce, GONZALEZ-ANGULO, Ana, HENNESSY, Bryan, MILLS, Gordon B, TAN, Chen-Keat, SLINGERLAND, Joyce M
• Format: Article
• Language: English
• Subjects: Anastrozole; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; aromatase inhibitor; Aromatase Inhibitors - administration & dosage; Benzodioxoles - administration & dosage; Biological and medical sciences; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; CSK Tyrosine-Protein Kinase; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Drug Resistance, Neoplasm; Female; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Ki-67 Antigen - metabolism; Mammary gland diseases; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases - metabolism; Nitriles - administration & dosage; p27; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Quinazolines - administration & dosage; Signal Transduction - drug effects; Src inhibitor; src-Family Kinases; Triazoles - administration & dosage; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-3127

Purpose: Antiestrogens are used to treat estrogen receptor (ER)-α-positive breast cancers and cause a p27-dependent G 1 arrest. Estrogen-bound ER recruits Src to mediate proteolysis of p27 and drive cell proliferation. Here, we tested the antitumor efficacy of combined Src and aromatase inhibition for ER-positive breast cancer. Experimental Design: Antiproliferative effects of the aromatase inhibitor, anastrozole, and Src inhibitor, AZD0530, alone or in combination were tested in vitro and in vivo on aromatase-transfected MCF-7Arom5 xenografts. Xenografts were analyzed by immunohistochemistry and proteomic analysis to identify potential biomarkers of drug response and resistance. Results: AZD0530 and anastrozole together increased p27 and caused greater G 1 cell cycle arrest than either drug alone. AZD0530 monotherapy initially retarded xenograft growth in vivo , but drug resistance rapidly emerged. Combined anastrozole/AZD0530 reduced drug resistance and showed greater antitumor efficacy in vivo with greater Src and epidermal growth factor receptor inhibition and a greater increase in p27 and reduction of Ki-67 than either drug alone, supporting further evaluation of these putative predictors of response to combined Src/aromatase inhibition in vivo . Anastrozole alone stimulated Src activity both in vitro and in vivo . AZD0530-resistant tumors showed activation of bypass pathways including MEK and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin, raising the possibility that MEK, mammalian target of rapamycin (mTOR), or PI3K inhibitors may augment Src inhibitor efficacy. Conclusions: These data support clinical investigation of anastrozole-AZD0530 therapy for postmenopausal ER-positive breast cancer. Loss of p27 and increased Ki-67 may predict response and further clinical studies should evaluate for activation of bypass pathways including MEK and PI3K pathways during Src inhibitor therapy.