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Oncogene
07, 2023;42 (28): 2207-2217.

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

Delong Meng, Xin Zhao, Yu Chi Yang, Albertas Navickas, Ciara Helland, Hani Goodarzi, Mallika Singh, Sourav Bandyopadhyay
Author Information
  1. Delong Meng: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
  2. Xin Zhao: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
  3. Yu Chi Yang: Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA. ORCID
  4. Albertas Navickas: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94158, USA.
  5. Ciara Helland: Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA.
  6. Hani Goodarzi: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94158, USA.
  7. Mallika Singh: Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA.
  8. Sourav Bandyopadhyay: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA. Sourav.Bandyopadhyay@ucsf.edu.
PMID: 37264081 DOI: 10.1038/s41388-023-02737-z

Abstract

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. Complete suppression of mTORC1 by RMC-6272 causes apoptosis in ER+/HER2- breast cancer cell lines, particularly in those that harbor mutations in PIK3CA or PTEN, due to inhibition of the rapamycin resistant, mTORC1 substrate 4EBP1 and reduction of the pro-survival protein MCL1. RMC-6272 reduced translation of ribosomal mRNAs, MYC target genes, and components of the CDK4/6 pathway, suggesting enhanced impairment of oncogenic pathways compared to the partial mTORC1 inhibitor everolimus. RMC-6272 maintained efficacy in hormone therapy-resistant acquired cell lines and patient-derived xenografts (PDX), showed increased efficacy in CDK4/6 inhibitor treated acquired resistant cell lines versus their parental counterparts, and was efficacious in a PDX from a patient experiencing resistance to CDK4/6 inhibition. Bi-steric mTORC1-selective inhibition may be effective in overcoming multiple forms of therapy-resistance in ER+ breast cancers.

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Grants

  1. U54 CA224081/NCI NIH HHS

MeSH Term

Humans
Female
Mechanistic Target of Rapamycin Complex 1
Breast Neoplasms
Multiprotein Complexes
TOR Serine-Threonine Kinases
Mechanistic Target of Rapamycin Complex 2
Sirolimus
Drug Resistance
Cell Line, Tumor
Cell Proliferation

Chemicals

Mechanistic Target of Rapamycin Complex 1
Multiprotein Complexes
TOR Serine-Threonine Kinases
Mechanistic Target of Rapamycin Complex 2
Sirolimus
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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