Abstract P5-02-24: Targeting FOXK2 signaling in breast cancers with FOXK2 amplification/overexpression and PIK3CA oncogenic mutations: a promising therapeutic strategy?

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Abstract Oncogene activation through DNA amplification or overexpression plays a critical role in cancer initiation and progression. Chromosome 17 harbors numerous cancer-associated genetic anomalies, some of which are strongly linked to poor prognosis in breast cancer patients. The FOXK2 gene, located on 17q25, encodes a transcription factor with a forkhead DNA binding domain. Integrative analyses of publicly available genomic datasets reveal that FOXK2 is frequently amplified and overexpressed in breast cancer, correlating with poor overall survival. FOXK2 knockdown via shRNA significantly inhibited the proliferation, migration, and anchorage-independent growth of breast cancer cells, causing G0/G1 cell cycle arrest. The C-terminal nuclear localization signal (NLS) is crucial for FOXK2's oncological function. Additionally, FOXK2 knockdown in MCF7 breast cancer cells delayed tumor growth in a xenograft mouse model. Inhibiting FOXK2 expression also sensitized breast cancer cells to frontline chemotherapy agents, including doxorubicin, 5-fluorouracil, and etoposide in vitro. Co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induced the transformation of non-tumorigenic MCF-10A cells, suggesting that FOXK2 acts as an oncogene in breast cancer and contributes to PI3KCA-driven tumorigenesis. CCNE2, PDK1, and ESR1 were identified as direct transcriptional targets of FOXK2 in MCF-7 cells. Moreover, co-inhibition of FOXK2 function, either through knockdown or inhibition of its transcriptional targets (CCNE2/CDK2 by Dinaciclib or PDK1 by DCA) and PI3KCA by alpelisib, had synergistic anti-tumor effects in breast cancer cells with FOXK2 overexpression and PI3KCA oncogenic mutations. FOXK2 functional inhibition by the CDK2 inhibitor Dinaciclib enhanced the tumor-suppressive effect of alpelisib in a MCF7 breast cancer xenograft mouse model. These findings provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis. The combination of PIK3CA and CCNE2/CDK2 inhibition by alpelisib and Dinaciclib offers a potential therapeutic strategy for breast cancer with FOXK2 overexpression and PIK3CA oncogenic mutation. Citation Format: Hong Zhang, Yang Yu, Weng-Ming Cao, Feng Cheng, Edaise da silva, Higinio Dopeso, Hui Chen, Xiaosong Wang, Chunchao Zhang. Targeting FOXK2 signaling in breast cancers with FOXK2 amplification/overexpression and PIK3CA oncogenic mutations: a promising therapeutic strategy? [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-02-24.

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