Silencing Kinase Interacting Stathmin Gene Enhances Erlotinib Sensitivity by Inhibiting Serine 10 p27 Phosphorylation in EGFR-expressing Breast Cancer

• Published in: Molecular cancer therapeutics 2010-11, Vol.9 (11), p.3090-3099
• Main Authors: Zhang, Dongwei, Tari, Ana M., Akar, Ugur, Arun, Banu K., LaFortune, Tiffany A., Nieves-Alicea, Rene, Hortobagyi, Gabriel N., Ueno, Naoto T.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-10-0362

The epidermal growth factor receptor (EGFR) signaling pathway has emerged as a promising target for cancer therapy. EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib have been approved for cancer treatment but have demonstrated very limited activity in breast cancer patients. Clarifying the molecular mechanism underlying resistance to EGFR-TKIs could lead to more effective treatment against breast cancer. We previously reported that the sensitivity of breast cancer cells to erlotinib is partially dependent on p27 and that cytoplasmic localization of p27 is associated with erlotinib resistance. In the present study, we found that erlotinib induces p27 phosphorylation at serine (S) 10, and S10 p27 phosphorylation leads to erlotinib resistance in EGFR-expressing breast cancer. Inhibiting S10 phosphorylation of p27 by knocking down human kinase interacting stathmin (KIS), a nuclear protein that can phosphorylate p27 at S10, led to p27 accumulation in the nucleus and enhanced erlotinib-mediated cytotoxicity. Further, in vivo KIS gene silencing enhanced the antitumor activity of erlotinib in an orthotopic breast cancer xenograft model. KIS depletion also enhanced erlotinib sensitivity in erlotinib-resistant EGFR-expressing triple-negative breast cancer cells. Our study provides a rationale for the development of combinations of erlotinib with KIS inhibition to overcome EGFR-TKI resistance in EGFR-expressing breast cancer.