Abstract 555: ERBB4 upregulation in a taxol-resistant triple-negative breast cancer cell line

Abstract Resistance to chemotherapy remains an unfavorable obstacle to effective cancer treatment. Although paclitaxel is one of commonly used chemotherapeutic agents in the treatment of triple-negative breast cancer (TNBC), resistance mechanisms are not fully understood. In this study, we found that ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) was substantially upregulated in T50RN, a paclitaxel-resistant cell clone established from the human TNBC cell line MDA-MD-231. We thus aimed to explore whether and how ERBB4 may modulate T50RN cell resistance to paclitaxel. The T50RN cell was obtained by exposing human TNBC cell line MDA-MB-231 to stepwise escalating paclitaxel concentration from 0.5 to 50 nM and then the resistant cell line T50RN was selected and expanded. The IC50 of paclitaxel was 2 and >100 nM in MDA-MB-231 and T50RN cells respectively. Treatment of the cells with ERBB inhibitors, sfatinib, allitinib, or PF299804, in sub-lethal concentration only induced a small additive effect on paclitaxel cytotoxicity in MDA-MB-231 cells, but dramatically enhanced paclitaxel cytotoxicity in T50RN cells. Since only the expression of ERBB4 was significantly upregulated in T50RN cells, the expression of EGFR1 was equally high in MDA-MB-231 and T50RN cells, and ERBB2 and ERBB3 were low in both cells, ERBB4 might play a critical role on the effect of the three ERBB inhibitors. In addition, the three inhibitors also significantly enhanced paclitaxel-induced spindle abnormalities in T50RN cells but had no effect in MDA-MB-231 cells. Depletion of ERBB4 with shRNA also significantly reduced the cell growth ability of T50RN but not MDA-MB-231 on soft agar. These results suggest that ERBB4 may play a critical role in paclitaxel resistance in T50RN cells. Further elucidation of how ERBB4 is induced in T50RN cells and how ERBB4 regulates cell resistance might provide leads to overcome paclitaxel resistance. Citation Format: Ling-Huei Yih, Hsiao-Hui Kuo, Tsai-Ming Lu. ERBB4 upregulation in a taxol-resistant triple-negative breast cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 555.