ArticleFrontiers in immunology2025
Targeting the KLF5/PI3K/AKT axis as a therapeutic strategy to overcome neoadjuvant chemoresistance in colorectal cancer.
Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Pan-cancer analysis reveals HDAC1 as a key regulator of immune infiltration and T cell exhaustion.Discover oncology · 2026Article
- Dynamin 1 promotes colorectal cancer progression by activating the PI3K/Akt signaling pathway.Journal of translational medicine · 2025Article
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Authors and funding
9 authors.
Funding
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Abstract
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.
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