ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1593639
This article is part of the Research TopicIntegrating Molecular Mechanisms, Immunotherapy, and Drug Sensitivity in Cancer Immunology and OncologyView all 29 articles
Targeting the KLF5/PI3K/AKT axis as a therapeutic strategy to overcome neoadjuvant chemoresistance in colorectal cancer
Provisionally accepted
Meiling Gao1
Jiahao Qian1
Ping Xia1
Wancheng Liu2Yunjia Jiang1Yuchang Xia1Xin Yao1
Qingqing Jiao1*
Minggang Wei1*- 1The First Affiliated Hospital of Soochow University, Suzhou, China
- 2Qilu Hospital, Shandong University, Jinan, Shandong Province, China
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Background: Oxaliplatin-based neoadjuvant chemotherapy (NAC) is the standard treatment for advanced colorectal cancer (CRC), yet resistance to NAC poses a significant clinical challenge. Methods: To investigate the mechanisms of chemoresistance, we analyzed single-cell RNA sequencing (scRNA-seq) data from CRC patients undergoing NAC. Comprehensive analyses, including InferCNV, differentially expressed genes analysis, pathway enrichment, cell communication, and SCENIC were performed. High-throughput drug screening identified potential therapeutic candidates targeting chemoresistance pathways, and the efficacy of targeting the KLF5/PI3K/AKT axis in combination with oxaliplatin was explored in animal models. Results: NAC effectively reduced tumor burden and enhanced T_NK cell infiltration in responsive tumors. Notably, NAC-resistant cell clusters exhibited activation of fatty acid-related metabolic pathways and demonstrated limited immune infiltration. Transcriptional analysis identified KLF5 as a potential driver of chemotherapy resistance. Based on these findings, we developed a KLF5 regulon-associated risk score model with significant potential for predicting CRC patient prognosis. Mechanistically, KLF5 activation of the PI3K/AKT pathway conferred chemoresistance in CRC cells. Through high-throughput screening, GDC-0941, a PI3K/AKT inhibitor, emerged as a promising therapeutic agent that synergistically enhanced oxaliplatin efficacy and overcame resistance in preclinical models. Conclusions: Targeting the KLF5/PI3K/AKT axis may enhance chemotherapy efficacy and overcome drug resistance in CRC.
Keywords: colorectal cancer, Oxaliplatin resistance, KLF5, GDC-0941, Neoadjuvant chemotherapy, PI3K/Akt pathway, chemoresistance
Received: 14 Mar 2025; Accepted: 18 Jun 2025.
Copyright: © 2025 Gao, Qian, Xia, Liu, Jiang, Xia, Yao, Jiao and Wei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qingqing Jiao, The First Affiliated Hospital of Soochow University, Suzhou, China
Minggang Wei, The First Affiliated Hospital of Soochow University, Suzhou, China
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