CRISPR screens reveal MCT1-driven metabolic escape from SMAD3 inhibition as a therapeutic vulnerability

Abstract

Resistance to therapy remains a critical challenge in cancer. This is exemplified by TGF-β pathway inhibitors which, despite broad clinical testing, have failed to deliver survival benefit. More precise SMAD3 targeting has shown preclinical promise, yet resistance mechanisms to SMAD3 inhibition remain entirely unknown. Using complementary genome-wide CRISPR activation and knockout screens, we discover that cancer cells escape SMAD3 inhibition through metabolic reprogramming. Strikingly, this escape is driven not by transcriptional bypass but by the lactate transporter MCT1, with the effect preserved across BRAF-mutated melanoma, KRAS-mutated lung adenocarcinoma, and mouse melanoma. Mechanistically, SMAD3 inhibition creates energetic stress that cancer cells exploit through MCT1. By conferring metabolic flexibility and switching toward glycolysis under drug pressure, MCT1 increases anabolic activity to drive lipid and cholesterol synthesis. Pharmacological and genetic MCT1 inhibition synergizes strongly with SMAD3 blockade to impair tumor viability in BRAF-mutated melanoma, while suppressing drug-tolerant cell emergence in BRAF inhibitor-resistant cells. Critically, this synergy extends to preclinical models, where co-inhibition of SMAD3 and MCT1 potently reduces tumor growth in vivo. Given the additional and well-established role of MCT1 in shaping the tumor immune microenvironment via lactate transport, these results position MCT1 as both a metabolic and immunological target and provide a strong rationale for the repurposing of TGF-β/SMAD3 pathway inhibitors in combination.

A metabolic perspective on eIF1A and eIF3B inhibition as a potential therapeutic strategy in psoriasis
N. Bordag, B. M. R. Bourgeois, T. Madl +2
bioRxiv8 Oct 2026PreprintCC BYFull textMolecular biology & gene regulationbioRxiv
Structural basis for loop-dependent inhibition by AcrIIC1 anti-CRISPR proteins
Shen Wang, Zhiyu Zhang, Chenyu Luan +8
Nature Communications16 Oct 2026Peer-reviewedCC BY-NC-ND 4.0Full textMolecular biology & gene regulationCrossref
Genome-wide CRISPR screening reveals a chromatin-to-mitochondrial dependency architecture underlying Galunisertib-induced OXPHOS vulnerability
Naoufal Akla, Anes Boudah, Marieme Thioro Faye +2
Scientific Reports2 Oct 2026Peer-reviewedCC BY 4.0Full textMolecular biology & gene regulationCrossref
Visualizing the Atomic-Level Impact of Anti-CRISPR II–C1 Inhibition on Geo Cas9 with Integrated Structural Biophysics
Alexa L. Knight, Helen B. Belato, Praise Lasekan +7
JACS Au22 Oct 2026Peer-reviewedCC BY-NC-ND 4.0Full textMolecular biology & gene regulationCrossref
CasNano: An ultracompact CRISPR-Cas12f with a GC-rich PAM for epigenome editing with therapeutic potential
Dongkyeong Kim, Chia-Wei Huang, Richard Pan +5
Molecular therapy. Nucleic acids18 Sep 2026Peer-reviewedCC BYFull textMolecular biology & gene regulationEurope PMC

Cite

BibTeX RIS

BibTeX

@article{matvere2026crispr,
  title = {{CRISPR screens reveal MCT1-driven metabolic escape from SMAD3 inhibition as a therapeutic vulnerability}},
  author = {Antti Matvere and Grégory Menchon and Laetitia Martinetti and Amelie Menant and Loan Callac and Hugo Ferrari and Ulrich Jarry and Mathilde Gourdel and Aurélien Bore and Morgane Chassignolle and Victor Le Bars and Edouard Cadieu and Thomas Derrien and Marc Aubry and David Gilot and Rémy Pedeux},
  journal = {Molecular Cancer},
  year = {2026},
  month = sep,
  doi = {10.1186/s12943-026-02757-9},
  url = {https://hal.science/hal-05746932v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - JOUR
TI  - CRISPR screens reveal MCT1-driven metabolic escape from SMAD3 inhibition as a therapeutic vulnerability
AU  - Antti Matvere
AU  - Grégory Menchon
AU  - Laetitia Martinetti
AU  - Amelie Menant
AU  - Loan Callac
AU  - Hugo Ferrari
AU  - Ulrich Jarry
AU  - Mathilde Gourdel
AU  - Aurélien Bore
AU  - Morgane Chassignolle
AU  - Victor Le Bars
AU  - Edouard Cadieu
AU  - Thomas Derrien
AU  - Marc Aubry
AU  - David Gilot
AU  - Rémy Pedeux
PY  - 2026
DA  - 2026/09/11
JO  - Molecular Cancer
DO  - 10.1186/s12943-026-02757-9
UR  - https://hal.science/hal-05746932v1
AB  - Resistance to therapy remains a critical challenge in cancer. This is exemplified by TGF-β pathway inhibitors which, despite broad clinical testing, have failed to deliver survival benefit. More precise SMAD3 targeting has shown preclinical promise, yet resistance mechanisms to SMAD3 inhibition remain entirely unknown. Using complementary genome-wide CRISPR activation and knockout screens, we discover that cancer cells escape SMAD3 inhibition through metabolic reprogramming. Strikingly, this escape is driven not by transcriptional bypass but by the lactate transporter MCT1, with the effect preserved across BRAF-mutated melanoma, KRAS-mutated lung adenocarcinoma, and mouse melanoma. Mechanistically, SMAD3 inhibition creates energetic stress that cancer cells exploit through MCT1. By conferring metabolic flexibility and switching toward glycolysis under drug pressure, MCT1 increases anabolic activity to drive lipid and cholesterol synthesis. Pharmacological and genetic MCT1 inhibition synergizes strongly with SMAD3 blockade to impair tumor viability in BRAF-mutated melanoma, while suppressing drug-tolerant cell emergence in BRAF inhibitor-resistant cells. Critically, this synergy extends to preclinical models, where co-inhibition of SMAD3 and MCT1 potently reduces tumor growth in vivo. Given the additional and well-established role of MCT1 in shaping the tumor immune microenvironment via lactate transport, these results position MCT1 as both a metabolic and immunological target and provide a strong rationale for the repurposing of TGF-β/SMAD3 pathway inhibitors in combination.
SN  - 1476-4598
ER  -

Abstract

Related

Cite