2. Academic Validation
  3. PKM2 Lactylation Promotes Colorectal Cancer Vasculogenic Mimicry and Bevacizumab Resistance by Facilitating FOSL1 Super-enhancer Formation

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

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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