Symposium 3-2:

-Prediction of response and tolerance of cacer drugs-

The role of PI3-K/Akt pathway in regulating the breast cancer stem cells and therapeutic resistance

Hasan Korkaya, DVM, PhD

University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

Despite recent advances in the treatment of breast cancer, the fact remains that once metastatic, the disease is incurable. We and others have provided strong support for the cancer stem cell (CSC) hypothesis which suggests that breast cancers are driven by a subpopulation of cells which display stem cell properties. Studies by our group and others have demonstrated a relative resistance of CSCs to chemotherapy and radiation therapy. One of the most signifi cant advances in breast cancer therapeutics has been the development of HER2 targeted therapies for treatment of HER2 overexpressing breast cancers. Trastuzumab in the adjuvant setting has demonstrated signifi cant impact on reducing tumor recurrence. However, onethird of HER2-positive tumors do not respond to HER2 targeted agents and resistance may develop in patients with chronic exposure. Studies have found that nearly 50% of patients who respond to HER2 targeted agents relapse within a year. Although the mechanism of resistance to HER2 targeted agents is not entirely clear, increasing evidence indicates that this resistance may be associated with loss of PTEN (phosphotase and tensin homolog), the gain of function of somatic mutations of PI3KA or truncation of the extracellular domain of HER2. We recently demonstrated in a set of breast cancer cell lines that trastuzumab-sensitive cell lines show decrease in CSC population, however the CSC population in resistant cell lines is not effected by trastuzumab suggesting a role in resistance.
We generated a mouse model for trastuzumab resistance utilizing engineered MCF7 cell lines overexressing HER2 or PTEN knockdown in addition to HER2 overexpression. PTEN deletion in HER2 expressing cells resulted in increased CSC population as compared to HER2 overexpression alone. PTEN deletion also increased the motility of cells by several fold in vitro. When we tested these cell lines for trastuzumab response in vitro, although the treatment of HER2 overexpressing cells decreased the CSC population had no effect in cell lines with PTEN deletion and HER2 overexpression. Our in vivo experiments demonstrated that PTEN deletion results in accelerated tumor growth and development of extensive metastasis from primary tumors, properties not found in parent or HER2 overexpressing MCF7 cells. We observed an extensive metastasis to liver in mice with primary tumor generated from PTEN deleted and HER2 overexpressing cells. We are in the process of analyzing the trastuzumab resistance and currently testing the combination of trastuzumab with Akt inhibitor in these mouse models and results will be discussed in the AACR annual meeting.
These studies suggest that the remarkable clinical effi cacy of HER2 inhibitors may be due to their ability to target breast CSCs and combination of with other therapies such as Akt inhibitors may benefi t patients with trastuzumab resistance.

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