PKM2 Lactylation Promotes Colorectal Cancer Vasculogenic Mimicry and Bevacizumab Resistance by Facilitating FOSL1 Super-enhancer Formation

  • Cancer Res. 2026 Jun 1;86(11):2759-2776. doi: 10.1158/0008-5472.CAN-25-3520.
Weihao Li  #  1  2 ,  Jianhong Peng  #  1  2 ,  Jiahua He  #  1  2 ,  Leen Liao  1  2 ,  Da Kang  1  2 ,  Weili Zhang  1  2 ,  Weifeng Wang  1  2 ,  Ruowei Wang  1  2 ,  Song Wang  1  2 ,  Yuanbin Liao  1  2 ,  Long Yu  1  2 ,  Qingjian Ou  1  2 ,  Yujing Fang  1  2 ,  Xiaojun Wu  1  2 ,  Peirong Ding  1  2 ,  Zhizhong Pan  1  2 ,  Chi Zhou  1  2 ,  Junzhong Lin  1  2
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2. Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • # Contributed equally.
PMID: 41784617 DOI: 10.1158/0008-5472.CAN-25-3520
Abstract

Despite the clinical utility of bevacizumab in advanced Colorectal Cancer, resistance remains a major challenge. In this study, we unveiled a lactate-mediated mechanism driving vasculogenic mimicry (VM) and bevacizumab resistance through PKM2 lactylation. PKM2 lactylation at K206 by AARS1 promoted PKM2 nuclear translocation and interaction with FOSL1. PKM2 binding facilitated FOSL1-dependent super-enhancer formation and target gene transcription, which contributed to Colorectal Cancer cell VM. Genetic or pharmacologic inhibition of PKM2 lactylation disrupted VM and synergized with bevacizumab in patient-derived preclinical models, significantly improving therapeutic efficacy. Together, this study reveals lactylation as a metabolic switch linking Cancer glycolytic reprogramming to transcriptional rewiring and proposes targeting PKM2 lactylation to enhance the antitumor activity of bevacizumab in Colorectal Cancer.

Significance: PKM2 lactylation mediates vasculogenic mimicry by facilitating FOSL1-dependent super-enhancer formation and represents a potential target to improve the clinical efficacy of bevacizumab in Colorectal Cancer patients.

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