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GATOR1 complex controls cisplatin sensitivity.

Zhenrui Pan^1,2, Hanxiao Zhang¹, Xia Xiao¹

¹CNRS UMR9018, Université Paris-Saclay, Gustave Roussy, Villejuif, France.

Cell Death & Disease

|December 30, 2025

Summary

This summary is machine-generated.

The GATOR1 complex, not just NPRL2, is crucial for cisplatin resistance in cancers. Deleting GATOR1 components increases resistance, while overexpression restores sensitivity, offering new therapeutic targets for chemotherapy resistance.

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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo

Published on: February 6, 2015

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

Cisplatin is a key chemotherapy for epithelial cancers, but drug resistance is a major obstacle.
Low NPRL2 expression was previously linked to cisplatin resistance.
NPRL2, NPRL3, and DEPDC5 form the GATOR1 complex, regulating mTORC1, which is often dysregulated in cisplatin-resistant cancers.

Purpose of the Study:

To investigate the role of the GATOR1 complex in cisplatin resistance beyond NPRL2.
To compare intrinsic and acquired cisplatin resistance models.
To identify molecular mechanisms underlying GATOR1-mediated cisplatin resistance.

Main Methods:

Utilized BEAS-2B cells with GATOR1 deletions as an intrinsic resistance model.
Employed cisplatin-resistant non-small cell lung cancer cell lines (A549, H460, H1975) for acquired resistance.
Analyzed transporter expression (ATP7A, CTR2, LRRC8A), DNA damage response, mTORC1 activity, and performed transcriptomic analysis.

Main Results:

Deletion of any GATOR1 component confers cisplatin resistance; overexpression restores sensitivity.
GATOR1 deletion upregulates cisplatin efflux (ATP7A) and downregulates influx (CTR2, LRRC8A) transporters.
Cells with GATOR1 deletions show increased DNA damage response and mTORC1 activity, hindering cisplatin-DNA adduct formation.

Conclusions:

The GATOR1 complex, not solely NPRL2, plays a significant role in both intrinsic and acquired cisplatin resistance.
Altering GATOR1 component expression or inhibiting mTORC1 can modulate cisplatin sensitivity.
GATOR1's novel function in chemoresistance warrants consideration for developing new therapeutic strategies against cisplatin resistance.