Resistance to molecular targeted therapy is a major challenge facing breast cancer patients and unfavorably impacts clinical outcomes, leading to hundreds of thousands of deaths yearly. Resistance to cancer therapies arises from many factors. One of the key factors driving resistance is oncogenes which initiate pro-growth, pro-survival and metastatic programs that enable cancers escape various therapies. In HER2+ breast cancer, the oncogene HER2 is the master driver of this tumor. Trastuzumab effectively targets HER2. While this is generally successful, some patients who have HER2+ breast cancer develop resistance to trastuzumab and there are limited treatment options for them. Moreover, for low HER2+ expressing breast cancer, there are limited treatment options for them. And in African American women who have HER2+ breast cancer, there is disparity in their treatment outcomes. We have discovered that 3’UTR of HER2 is enriched with poly U stabilizing AU rich elements (ARE). We have developed a novel technology wherein we engineered the stabilizing HER2 3’UTR ARE motifs to destabilizing motif in HER2+ and HER2+ trastuzumab resistant breast cancer cells to control HER2 transcript. We achieved complete degradation of HER2 within 4-8 days in HER2+ wildtype breast cancer cells and 9-11 days in HER2+ trastuzumab resistant breast cancer cells. We had loss of cancer cell viability by more than 90%. We also show that control of HER2 transcript downregulated HER2-dependent kinases, transcription factors, and HER2 interactome. Mechanistically, the control of HER2 transcript was achieved by destabilized ARE sequence specificity which triggered the proteins PARN, XRN1 and CNOT1 to degrade HER2 transcript and this led to induction of active caspase 3/7, reduction of cell size, and severe distortion and disruption of the cancer cell membrane leading to cell death. Taken together, we have a developed a novel approach to control HER2 transcript expression both on spatial and temporal scale. This novel approach offers applications for targeting HER2+ trastuzumab resistant breast cancer as well as other cancers resistant to HER2 targeted therapy and driven by pervasive oncogenic signals.

Citation Format: Chidiebere U. Awah, Fu Dong, Fayola Levine, Leonard Ash, Yana Glemaud, Olorunseun Ogunwobi. Engineered destabilized AU rich elements on the 3UTR of HER2 degrades HER2, inhibits proliferation, and induces apoptosis in HER2 positive trastuzumab resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1788.