Abstract 192: Targeting the protein kinase Hunk in HER2+ resistant breast cancer

Despite the initial success of common HER2 inhibitors used in the clinic, including trastuzumab and lapatinib, HER2 positive (HER2+) breast cancer cells often acquire resistance through mechanisms that continue to remain poorly understood. A number of signaling molecules, which act downstream of HER2, including PI3K, Akt, JNK, and Hormonally-Upregulated Neu-associated Kinase (Hunk), are thought to contribute to resistance. Our recent studies indicate that targeting Hunk via shRNA in HER2+breast cancer cells that are sensitive to HER2 inhibitors (BT474) and cells that are resistant (JIMT) leads to increased caspase-3 activity in vitro and impaired tumor growth in vivo. In addition, we find that targeting Hunk not only sensitizes HER2+ cells to apoptosis, but also impairs autophagy, as indicated by decreased LC3BII expression, the lipidated form of LC3B which signifies active autophagy. Because elevated Hunk protein expression correlates with poorer prognosis, and since Hunk knockdown impairs autophagy, it is possible that Hunk acts to upregulate autophagy thereby contributing to the development of resistance. We have also found that the kinase JNK plays a role in resistance in HER2+ breast cancer cells, and demonstrate that JNK inhibition via a pan-JNK inhibitor impairs tumor growth of JIMT cells. We further show that co-targeting of JNK and HUNK results in greater cell death and significantly reduced tumor growth than either individual treatment in the JIMT-1, HER2+ resistant cell line, as well as a HER2+ line that was engineered to be lapatinib resistant, BT474-LR. Overall, our results indicate that targeting Hunk in HER2+ breast cancer not only alters autophagy and impairs tumor growth, but that co-targeting Hunk and JNK shows greater therapeutic effects on reducing tumor growth and inducing cell death. Citation Format: Joelle Zambrano, Kendall Phelps-Polirer, Melissa Abt, Elizabeth Yeh. Targeting the protein kinase Hunk in HER2+ resistant breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 192.