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PreprintCC BYbioRxiv

MCT1 activity defines an aggressive metabolic phenotype and therapeutic target in non-small cell lung cancer

  • R. B. Cameron
  • K. E. Shema
  • N. Dubois
  • M. G. Clare
  • N. G. Hammond
  • M. Kaur
  • B. K. Chang
  • E. G. Schechter
  • J. Hsiang
  • Z. Marczenia
  • M. C. Garassino
  • L. Cai
5 more authors
  • C. M. Bestvina
  • T. P. Mathews
  • A. Tasdogan
  • H. Shah
  • B. Faubert1
  1. 1University of Chicago
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Abstract

Lactate uptake through monocarboxylate transporter 1 (MCT1) is associated with aggressive disease in non-small cell lung cancer (NSCLC), but how lactate transport supports tumor metabolism remains incompletely understood. Integrating stable isotope tracing, metabolomics, and transcriptomics across patient tumors, animal models, and cultured cells, we show that elevated lactate utilization and SLC16A1 expression correlate with worse clinical outcomes in NSCLC. Although MCT1 inhibition with AZD3965 does not significantly impair tumor growth as a monotherapy, it depletes purine-associated metabolite pools, alters redox balance, and induces a conserved transcriptional response involving MYC target dysregulation and suppression of nucleotide metabolism genes. Addition of exogenous hypoxanthine, or expression of the E. coli-derived NADH-producing enzyme soluble transhydrogenase, partially rescues the effects of MCT1 inhibition. Importantly, this metabolically compromised state sensitizes NSCLC to nucleotide-targeting chemotherapies, including pemetrexed. These findings reveal that MCT1 mediated lactate uptake sustains nucleotide homeostasis in NSCLC, and that its inhibition exposes a context-dependent vulnerability that can be leveraged to enhance chemotherapy efficacy.

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Cite

BibTeXRIS
BibTeX
@misc{cameron2026mct1,
  title = {{MCT1 activity defines an aggressive metabolic phenotype and therapeutic target in non-small cell lung cancer}},
  author = {R. B. Cameron and K. E. Shema and N. Dubois and M. G. Clare and N. G. Hammond and M. Kaur and B. K. Chang and E. G. Schechter and J. Hsiang and Z. Marczenia and M. C. Garassino and L. Cai and C. M. Bestvina and T. P. Mathews and A. Tasdogan and H. Shah and B. Faubert},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.20.752999},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.20.752999v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - MCT1 activity defines an aggressive metabolic phenotype and therapeutic target in non-small cell lung cancer
AU  - R. B. Cameron
AU  - K. E. Shema
AU  - N. Dubois
AU  - M. G. Clare
AU  - N. G. Hammond
AU  - M. Kaur
AU  - B. K. Chang
AU  - E. G. Schechter
AU  - J. Hsiang
AU  - Z. Marczenia
AU  - M. C. Garassino
AU  - L. Cai
AU  - C. M. Bestvina
AU  - T. P. Mathews
AU  - A. Tasdogan
AU  - H. Shah
AU  - B. Faubert
PY  - 2026
DA  - 2026/09/20
PB  - bioRxiv
DO  - 10.64898/2026.09.20.752999
UR  - https://www.biorxiv.org/content/10.64898/2026.09.20.752999v1
AB  - Lactate uptake through monocarboxylate transporter 1 (MCT1) is associated with aggressive disease in non-small cell lung cancer (NSCLC), but how lactate transport supports tumor metabolism remains incompletely understood. Integrating stable isotope tracing, metabolomics, and transcriptomics across patient tumors, animal models, and cultured cells, we show that elevated lactate utilization and SLC16A1 expression correlate with worse clinical outcomes in NSCLC. Although MCT1 inhibition with AZD3965 does not significantly impair tumor growth as a monotherapy, it depletes purine-associated metabolite pools, alters redox balance, and induces a conserved transcriptional response involving MYC target dysregulation and suppression of nucleotide metabolism genes. Addition of exogenous hypoxanthine, or expression of the E. coli-derived NADH-producing enzyme soluble transhydrogenase, partially rescues the effects of MCT1 inhibition. Importantly, this metabolically compromised state sensitizes NSCLC to nucleotide-targeting chemotherapies, including pemetrexed. These findings reveal that MCT1 mediated lactate uptake sustains nucleotide homeostasis in NSCLC, and that its inhibition exposes a context-dependent vulnerability that can be leveraged to enhance chemotherapy efficacy.
ER  -