Abstract PS16-10: Tao kinase 3 augment the resistance to microtubule-disrupting agents in breast cancer cells

Abstract

Abstract Breast cancer is the leading type of cancer in women worldwide. It is a heterogeneous disease that contains several subtypes with substantial differences in pathology and clinical outcome. With the advancements in imaging and targeted therapy, many patients with early stages of this disease have a great opportunity to be cured. However, recurrence or metastasis of tumor still occurs in patients even after successful primary treatment. Chemotherapy remains one of the most important treatment for advanced breast cancer. Anti-microtubule agents including taxanes, eribulin and vinca-alkaloids constitutes the major anti-breast cancer chemotherapeutic category, while chemoresistance remains a thorny issue for advanced disease. We aimed to discover novel candidate regulators for chemoresistance in breast cancer. A lentiviral-based, high-throughput shRNA platform was developed for screening the variation of global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells. The underlying molecular mechanisms was further explored by global phosphoprotein array and expression microarray. The serine/threonine kinase, TAO Kinase 3 (TAOK3), was identified from 724 kinase genes. Knockdown of TAOK3 exhibited the most profound reduction of IC50 values in response to paclitaxel treatment in breast cancer cells. High expression of TAOK3 was related to poor prognosis in breast cancer patients after adjuvant chemotherapy. Furthermore, the expression of TAOK3 also decreased the sensitivity to other anti-microtubule drugs, including eribulin and vinorelbine. Expression microarray analysis revealed that NF-κB signaling plays the major regulation roles in TAOK3-associated resistance. Taken together, our results showed that TAOK3 increases resistance to anti-microtubule drug through upregulating the NF-κB signaling in breast cancer. Inhibitors that disrupt TAOK3 and NF-κB signaling pathway may overcome the drug resistance for patients treated with anti-microtubule agents. Citation Format: Chih-Yeu Fang, Tsung-Ching Lai, Michael Hsiao. Tao kinase 3 augment the resistance to microtubule-disrupting agents in breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-10.