Methionine restriction plus vitamin B12 antagonism overcomes methionine independence for cancer therapy
Abstract
Methionine dependence represents a well-known metabolic vulnerability in cancer. Despite promising preclinical results, methionine restriction is impaired by the presence of methionine-independent cancer cells. After confirming both inter- and intra-tumoral heterogeneity in methionine dependence, we demonstrate that "methionine-independent" cells are rather "methionine self-sufficient," relying on the vitamin B12 (B12)-dependent methionine synthase (MTR) to sustain growth without exogenous methionine, which renders them highly vulnerable to B12 deprivation. Dual methionine and B12 deprivation produced synergistic cytotoxicity, inhibiting proliferation and inducing apoptosis across multiple cancer types and primary tumor cells, while sparing fibroblasts. This synergy persisted under moderate nutrient restriction, supporting translational potential. Moreover, dual therapy prevented the adaptive metabolic shift seen with methionine deprivation alone, avoiding rebound proliferation and resistance. In vivo, a methionine-restricted diet plus a synthesized B12 antagonist significantly suppressed growth of methionine-independent pancreatic xenografts without hematologic toxicity. These findings uncover a selective, synergistic anticancer strategy targeting methionine self-sufficiency.
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BibTeX
@article{lacombe2026methionine,
title = {{Methionine restriction plus vitamin B12 antagonism overcomes methionine independence for cancer therapy}},
author = {Valentin Lacombe and Jade Aurrière and Adélie Mellinger and Salim Khiati and Nicolas Giachetti and Flavien Bessaguet and Sarah Bellal and Pascal Reynier and Franck Geneviève and Geoffrey Urbanski and Guy Lenaers},
journal = {Cancer Letters},
year = {2026},
month = oct,
doi = {10.1016/j.canlet.2026.218723},
url = {https://hal.science/hal-05804322v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Methionine restriction plus vitamin B12 antagonism overcomes methionine independence for cancer therapy
AU - Valentin Lacombe
AU - Jade Aurrière
AU - Adélie Mellinger
AU - Salim Khiati
AU - Nicolas Giachetti
AU - Flavien Bessaguet
AU - Sarah Bellal
AU - Pascal Reynier
AU - Franck Geneviève
AU - Geoffrey Urbanski
AU - Guy Lenaers
PY - 2026
DA - 2026/10/17
JO - Cancer Letters
DO - 10.1016/j.canlet.2026.218723
UR - https://hal.science/hal-05804322v1
AB - Methionine dependence represents a well-known metabolic vulnerability in cancer. Despite promising preclinical results, methionine restriction is impaired by the presence of methionine-independent cancer cells. After confirming both inter- and intra-tumoral heterogeneity in methionine dependence, we demonstrate that "methionine-independent" cells are rather "methionine self-sufficient," relying on the vitamin B12 (B12)-dependent methionine synthase (MTR) to sustain growth without exogenous methionine, which renders them highly vulnerable to B12 deprivation. Dual methionine and B12 deprivation produced synergistic cytotoxicity, inhibiting proliferation and inducing apoptosis across multiple cancer types and primary tumor cells, while sparing fibroblasts. This synergy persisted under moderate nutrient restriction, supporting translational potential. Moreover, dual therapy prevented the adaptive metabolic shift seen with methionine deprivation alone, avoiding rebound proliferation and resistance. In vivo, a methionine-restricted diet plus a synthesized B12 antagonist significantly suppressed growth of methionine-independent pancreatic xenografts without hematologic toxicity. These findings uncover a selective, synergistic anticancer strategy targeting methionine self-sufficiency.
SN - 0304-3835
ER -