Sustained Oncogenic Signaling in the Cytostatic State Enables Targeting of Nonproliferating Persistent Cancer Cells

Lisa M. Kim, Paul Y. Kim, Yemarshet K. Gebreyohannes, Cheuk T. Leung

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

UNLABELLED: Many advanced therapeutics possess cytostatic properties that suppress cancer cell growth without directly inducing death. Treatment-induced cytostatic cancer cells can persist and constitute a reservoir from which recurrent growth and resistant clones can develop. Current management approaches primarily comprise maintenance and monitoring because strategies for targeting nonproliferating cancer cells have been elusive. Here, we used targeted therapy paradigms and engineered cytostatic states to explore therapeutic opportunities for depleting treatment-mediated cytostatic cancer cells. Sustained oncogenic AKT signaling was common, while nonessential, in treatment-mediated cytostatic cancer cells harboring PI3K-pathway mutations, which are associated with cancer recurrence. Engineering oncogenic signals in quiescent mammary organotypic models showed that sustained, aberrant activation of AKT sensitized cytostatic epithelial cells to proteasome inhibition. Mechanistically, sustained AKT signaling altered cytostatic state homeostasis and promoted an oxidative and proteotoxic environment, which imposed an increased proteasome dependency for maintaining cell viability. Under cytostatic conditions, inhibition of the proteasome selectively induced apoptosis in the population with aberrant AKT activation compared with normal cells. Therapeutically exploiting this AKT-driven proteasome vulnerability was effective in depleting treatment-mediated cytostatic cancer cells independent of breast cancer subtype, epithelial origin, and cytostatic agent. Moreover, transient targeting during cytostatic treatment conditions was sufficient to reduce recurrent tumor growth in spheroid and mouse models. This work identified an AKT-driven proteasome-vulnerability that enables depletion of persistent cytostatic cancer cells harboring PTEN-PI3K pathway mutations, revealing a viable strategy for targeting nonproliferating persistent cancer cell populations before drug resistance emerges.

SIGNIFICANCE: This study finds that sustained oncogenic signaling in therapy-induced cytostatic cancer cells confers targetable vulnerabilities to deplete persistent cancer cell populations and reduce cancer recurrence.

Original languageEnglish (US)
Pages (from-to)3045-3057
Number of pages13
JournalCancer Research
Volume82
Issue number17
DOIs
StatePublished - Sep 1 2022

Bibliographical note

Funding Information:
C.T. Leung reports grants from NIH/NCI, American Cancer Society Institutional Research Grant, and grants from University of Minnesota Foundation during the conduct of the study. No disclosures were reported by the other authors.

Funding Information:
The authors thank Drs. Kaylee Schwertfeger, Douglas Yee, Jon Coloff, and the entire Leung lab for their helpful discussions and Dr. Thomas Cattabiani at the Stevens Institute of Technology for editing the manuscript. They thank the staff at the University of Minnesota Genomics Center, the University Imaging Centers, and the Center for Mass spectrometry and Proteomics at the University of Minnesota. The work is supported by grant awards from University of Minnesota Foundation, Lisa Rosenthal Fund for Metastatic Breast Cancer Research, Amer-

Funding Information:
The authors thank Drs. Kaylee Schwertfeger, Douglas Yee, Jon Coloff, and the entire Leung lab for their helpful discussions and Dr. Thomas Cattabiani at the Stevens Institute of Technology for editing the manuscript. They thank the staff at the University of Minnesota Genomics Center, the University Imaging Centers, and the Center for Mass spectrometry and Proteomics at the University of Minnesota. The work is supported by grant awards from University of Minnesota Foundation, Lisa Rosenthal Fund for Metastatic Breast Cancer Research, American Cancer Society Institutional Research Grant (#124166-IRG-58–001–55-IRG36), and NCI (#R01CA200652).

Publisher Copyright:
©2022 American Association for Cancer Research.

Keywords

  • Animals
  • Apoptosis
  • Carcinogenesis
  • Cell Line, Tumor
  • Cytostatic Agents/pharmacology
  • Mice
  • Neoplasm Recurrence, Local
  • PTEN Phosphohydrolase/genetics
  • Phosphatidylinositol 3-Kinases/metabolism
  • Proteasome Endopeptidase Complex
  • Proto-Oncogene Proteins c-akt/metabolism

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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