Abstract 3736: IL6 feedback loop regulates breast cancer stem cells which mediate trastuzumab resistance

IL6 feedback loop regulates breast cancer stem cells which mediate trastuzumab resistance
Hasan Korkaya,1 April Davis,1 Maria Ouzounova,1 Fayaz Malik,1 Gwangil Kim,1,2 Ahmed A. Quraishi,1 Shawn G. Clouthier,1 Max S. Wicha,1
1Comprehensive Cancer Center, Department of Internal medicine, University of
Michigan, Ann Arbor, MI 48109, USA,
2Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam
463-712, Gyeonggi, Republic of Korea,

The development of HER2 targeting agents such as trastuzumab and lapatinib represents one of the greatest achievements in clinical oncology demonstrating the effectiveness of molecularly targeted therapeutics (2). Despite the clinical benefits of trastuzumab in improving progression free and overall survival, majority of patients demonstrate "intrinsic" resistance or develop "acquired" resistance within one-to-two years.
Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain to be investigated. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrated that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of breast cancer stem cell (CSC) population. We and others previously demonstrated that cytokines including IL6 and IL8 regulates breast cancer stem cell self-renewal. Furthermore, elevated serum levels of these cytokines in breast cancer patients strongly correlated with metastatic disease and therapeutic resistance. We therefore hypothesized that activation of IL6 feedback loop may mediate trastuzumab resistance. Utilizing these models, we demonstrated that long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. Recombinant IL6 or conditioned medium from high-IL6 secreting cells resulted in trastuzumab resistance in parental PTEN wild type cells expanding CSCs with EMT phenotype characterized by the CD44+/CD24- expression and EMT gene signature.
An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies have important clinical implications demonstrating that trastuzumab resistance may be mediated by an IL-6 inflammatory loop and suggest that blocking this loop represents a novel strategy to overcome trastuzumab resistance.
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