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A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

Meng D, Zhao X, Yang YC, Navickas A, Helland C, Goodarzi H, Singh M, Bandyopadhyay S · 2023 · Oncogene · Atlas ID MEN2023

What this study shows

RMC-6272, a bi-steric molecule with >25-fold selectivity for mTORC1 over mTORC2, completely suppresses mTORC1 (hitting the rapamycin-resistant substrate 4E-BP1) and overcomes hormone- and CDK4/6-inhibitor resistance in breast cancer cell lines and PDX -- the preclinical basis for the RMC-5552 selective-inhibitor clinical program.

Cited on mTOR drugs in development: RMC-5552

Abstract

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Activation of the PI3K-mTOR pathway is central to breast cancer pathogenesis including resistance to many targeted therapies. The mTOR kinase forms two distinct complexes, mTORC1 and mTORC2, and understanding which is required for the survival of malignant cells has been limited by tools to selectively and completely impair either subcomplex. To address this, we used RMC-6272, a bi-steric molecule with a rapamycin-like moiety linked to an mTOR active-site inhibitor that displays >25-fold selectivity for mTORC1 over mTORC2 substrates.

Read the full abstract on PubMed →

At a glance

Evidence type A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Human ER+/HER2- breast cancer cell lines; mouse patient-derived xenografts (PDX)); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type4 - Animal Study
Model systemHuman ER+/HER2- breast cancer cell lines; mouse patient-derived xenografts (PDX)
JournalOncogene
Year2023
Peer reviewedYes
Record last updated2026-10-01
SourceDOI 10.1038/s41388-023-02737-z · PMID 37264081 · Free full text (PMC10328828)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

InterventionRMC-6272 (bi-steric mTORC1-selective inhibitor)
TargetmTORC1 (4E-BP1), >25-fold selective over mTORC2
ModelHuman cell lines; mouse PDX
EffectOvercomes hormone- and CDK4/6-inhibitor drug resistance via complete mTORC1 suppression

In the Atlas

Related topics

Breast cancermTORC1mTORC24E-BP1

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Want to understand the biology behind this study? → Challenge 02: Why rapamycin does not switch mTORC1 off

Cite this paper

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Meng, D., Zhao, X., Yang, Y. C., Navickas, A., Helland, C., Goodarzi, H., Singh, M., & Bandyopadhyay, S. (2023). A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer. Oncogene. https://doi.org/10.1038/s41388-023-02737-z

@article{MEN2023,
  author       = {Meng, D. and Zhao, X. and Yang, Y. C. and Navickas, A. and Helland, C. and Goodarzi, H. and Singh, M. and Bandyopadhyay, S.},
  title        = {{A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer}},
  journal      = {Oncogene},
  year         = {2023},
  doi          = {10.1038/s41388-023-02737-z},
  note         = {PMID: 37264081},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper. 

Barton, O. (2026). Oliver's mTOR Atlas (record MEN2023) [Data set]. https://mtor-atlas.org/study/MEN2023/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_MEN2023,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record MEN2023},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/MEN2023/},
  doi          = {10.5281/zenodo.22059963}
}
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