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<p>Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.</p>

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Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月23日

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  • Deborah Y. Moss,
  • Connor N. Brown,
  • Andrew M. Shaw,
  • Christopher McCann,
  • Nikita Lewis,
  • Matilda Downs,
  • Rebecca Wurelly,
  • Ciara Cunningham,
  • Aaron Philips,
  • Niamh Doherty,
  • Sarah Gallagher,
  • William J. McDaid,
  • Andrew Roe,
  • Aisling Y. Coughlan,
  • Brenton Cavanagh,
  • Callum Ormsby,
  • Fiammetta Falcone,
  • Rachel McCole,
  • Scott Monteith,
  • Emily Rogan,
  • Sudhir B. Malla,
  • Alexandra J. Emerson,
  • Letitia Mohammed-Smith,
  • Shaun Sharkey,
  • Aoife Leonard,
  • Peter F. Gallagher,
  • Arindam Banerjee,
  • Sandra Van Schaeybroeck,
  • Sufyan Pandor,
  • Brian Quinn,
  • Brett Greer,
  • Christopher Elliott,
  • Sarah Maguire,
  • Aideen E. Ryan,
  • Philip D. Dunne,
  • Mary Mallon,
  • Stephanie Craig,
  • Omar Aftab,
  • Laura C. Greaves,
  • Bryan P. Marzullo,
  • Daniel A. Tennant,
  • Vicky Coyle,
  • Ian G. Mills,
  • Owen Sansom,
  • Tríona Ní Chonghaile,
  • Daniel B. Longley,
  • Simon S. McDade,
  • Melissa J. LaBonte,
  • Emma M. Kerr

摘要

Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.