Targeting Signal Transducers and Activators of Transcription-3 (STAT3) as a Novel Strategy in Sensitizing Breast Cancer to EGFR-Targeted Therapy

摘要

Our research effort in the past award year has resulted in several interesting findings that support the study hypothesis: deregulated EGFR and STAT3 pathways synergistically contribute to the malignant biology of breast cancer and that combined uses of anti-EGFR and anti- STAT3 treatments result in significantly increased breast cancer cell death compared to single agent treatments. First, we have created isogenic breast cancer cell lines to stably express modestly activated and highly activated STAT3, STATCA. Second, using these established isogenic breast cancer cell lines, we found that increased STAT3 activation rendered breast cancer cells resistant to EGFR targeted therapy. Third, we showed that STAT3 expression knock-down sensitized EGFR- expressing breast cancer cells to anti-EGFR therapy. Finally, our in vitro results showed that combined used of a STAT3 small molecular weight inhibitor AG490 and a clinically used EGFR inhibitor Iressa synergistically targeted EGFR- expressing breast cancer cells to anti-EGFR therapy.