97P - Interleukin-6 expression is involved in the response to HER2-targeted therapy in breast cancer

Date 07 May 2015
Event IMPAKT 2015
Session Welcome reception and Poster Walk
Topics Breast Cancer
Translational Research
Presenter Yun-Ju Chen
Citation Annals of Oncology (2015) 26 (suppl_3): 31-33. 10.1093/annonc/mdv121
Authors Y. Chen1, P. Chien2, H. Pan3, W. Huang4
  • 1Department Of Biological Science & Technology, I-Shou University, 824 - Kaohsiung/TW
  • 2Department Of Medical Research, E-DA Hospital, Kaohsiung/TW
  • 3Department Of Biological Science & Technology, I-Shou University, Kaohsiung/TW
  • 4Graduate Institute Of Cancer Biology, China Medical University Hospital, 404 - Taichung/TW

Abstract

Body

Overexpression of human epidermal growth factor receptor 2 (HER2) (also known as Neu, ErbB2, EGFR2) was detected in 20-25% of breast cancer patients. HER2-positve breast cancer is highly aggressive due to its critical oncogenic role in tumor progression. HER2 tyrosine kinase activity has also been reported to enhance breast tumor initiating cell (BTIC) expansion. Therefore, HER2-targeted therapies, such as HER2 tyrosine kinase inhibitor (TKI) lapatinib (GW572016, Tykerb®) have been approved and shown significant clinic benefits for these breast cancer patients. However, these patients eventually developed acquired resistance, severely limiting the therapeutic efficacy of HER2-targeted therapy. Understanding the molecular mechanisms underlying the acquired resistance is very helpful for developing novel strategies to circumvent the therapeutic hurdle. Interleukin-6 (IL-6), a multifunctional cytokine, has been reported to play important roles in tumor proliferation, metastasis, survival and resistance to cancer therapy. Our results showed that acquired lapatinib-resistant clones of HER2-positive cells continue proliferation and maintain stemness properties even though HER2 tyrosine kinase activity was almost abolished. Moreover, IL-6 production was elevated in these resistant clones in comparison to their parental cells. Deprivation of IL-6 expression reduced the BTIC population and subsequent cell viability of these lapatinib-resistant clones. Further analysis of downstream signaling driven by IL-6 revealed that STAT3 activation might be the major target. Interestingly, STAT3 activation also regulated IL-6 production, leading to the formation of an IL-6 inflammatory loop. Collectively, these results suggest that the survival signaling of breast cancer cells is switched from HER2 to IL-6 and thus confers lapatinib resistance. Blockage of IL-6 may be a potential strategy to overcome lapatinib resistance.

Disclosure: All authors have declared no conflicts of interest.