Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer

Sep 24, 2026

Uploaded by Eliana

EphA2 is described as a tyrosine receptor kinase highly expressed across human cancers and implicated in proliferation, migration, and invasion, yet its control of basal-like breast cancer stemness and chemoresistance remained unclear. The study identifies KLF5 as a direct transcription factor for EphA2 in BLBC, linking clinical expression patterns with disease biology. TNF-α is reported to enhance BLBC stemness via activation of the KLF5-EphA2 axis, while EphA2 phosphorylation at S897 drives chemoresistance. Inhibition by ALW-II-41-27 reduces EphA2 pS897 and stemness in vitro and increases xenograft sensitivity to PTX and DDP in vivo. Clinical samples show higher EphA2 pS897 in tumors with poorer response to neoadjuvant chemotherapy.

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CategoryHealthcare

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Ivyspring International Publisher InternationalJournal of Biological Sciences 2023; 19(6): 1861-1874. doi: 10.7150/ijbs.82567 Research Paper Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer Ping Zhao1\#, Jian Sun1\#, Xinwei Huang2\#, Xiangwu Zhang1, Xin Liu1, Rong Liu3, Guangshi Du4, Wenqiang Gan5,6, Chuanyu Yang5, Yiyin Tang1􀀍, Ceshi Chen1,5,7􀀍, Dewei Jiang5,6􀀍 1. The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118 China 2. Key Laboratory of The Second Affiliated Hospital of Kuming Medical College, Kunming, 650101, China 3. Translational Cancer Research Center, Peking University First Hospital, Beijing, 100034 China 4. Translational Medicine Research Center, Guizhou Medical University, Guiyang, 550025 China 5. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201 China 6. Kunming College of Life Sciences, University of the Chinese Academy of Sciences, Kunming, 650204 China 7. Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500 China \# Equal contribution 􀀍 Corresponding authors: Dewei Jiang, [jiangdewei@mail.kiz.ac.cn](jiangdewei@mail.kiz.ac.cn), [orcid.org/0000-](orcid.org/0000-)0002-7773-5449; Ceshi Chen, [chenc@kmmu.edu.cn](chenc@kmmu.edu.cn), [orcid.org/0000](orcid.org/0000)- 0001-6398-3516; Yiying Tang, [tyy1485@163.com](tyy1485@163.com)[ ](tyy1485@163.com)© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [http://ivyspring.com/terms](http://ivyspring.com/terms) for full terms and conditions. Received: 2023.01.11; Accepted: 2023.03.08; Published: 2023.03.21 Abstract Ephrin type-A receptor 2 (EphA2) is a member of the tyrosine receptor kinases, a family of membrane proteins recognized as potential anticancer targets. EphA2 highly expressed in a variety of human cancers, playing roles in proliferation, migration, and invasion. However, whether and how EphA2 regulates basal-like breast cancer (BLBC) cell stemness and chemoresistance has not been revealed. Here, KLF5 was proven to be a direct transcription factor for EphA2 in BLBC cells, and its expression was positively correlated in clinical samples from breast cancer patients. The inflammatory factor TNF-α could promote BLBC cell stemness partially by activating the KLF5-EphA2 axis. Moreover, phosphorylation of EphA2 at S897 (EphA2 pS897) induced by TNF-α and PTX/DDP contributes to chemoresistance of BLBC. Furthermore, the EphA2 inhibitor ALW-II-41-27 could effectively reduce EphA2 pS897 and tumor cell stemness in vitro and significantly enhance the sensitivity of xenografts to the chemotherapeutic drugs PTX and DDP in vivo. Clinically, tumor samples from breast patients with less response to neoadjuvant chemotherapy showed a high level of EphA2 pS897 expression. In conclusion, KLF5-EphA2 promotes stemness and drug resistance in BLBC and could be a potential target for the treatment of BLBC. Keywords: EphA2, TNF-α, KLF5, BLBC stem cells, Chemoresistance, ALW-II-41-27 Introduction As the most common malignant tumor, breast cancer poses a great threat to women's health worldwide[1] . Breast cancer is a highly heterogeneous group of tumors, of which basal-like breast cancer (BLBC) is a type of most malignant breast cancer, accounting for 10-20% of all breast cancers[2] . It is well known that BLBC is characterized by high heterogeneity, poor prognosis, and susceptibility to recurrence and metastasis[3] and is mainly treated through chemotherapy. Approximately 20% of patients with BLBC achieve pathological complete remission (pCR) after treatment with chemotherapeutic drugs such as taksol, anthracycline, and platinum

FAQs

What role does KLF5 play in basal-like breast cancer regarding EphA2?

KLF5 is proven to be a direct transcription factor for EphA2 in basal-like breast cancer cells, and its expression correlates positively with EphA2 in clinical samples.

How does TNF-α contribute to cancer stemness and chemoresistance in BLBC?

TNF-α promotes BLBC cell stemness partly by activating the KLF5-EphA2 axis. It also induces EphA2 phosphorylation at S897, which contributes to chemoresistance.

How does the EphA2 inhibitor ALW-II-41-27 affect treatment outcomes?

ALW-II-41-27 effectively reduces EphA2 pS897 and tumor cell stemness in vitro and significantly enhances xenograft sensitivity to PTX and DDP in vivo.

Sep 24, 2026

Uploaded by Eliana