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Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition

Gemma A Wilson1, Karla Vuina1, Georgina Sava2

  • 1Laboratory for Molecular Cell Biology, University College London, London, UK.

Molecular Cell
|November 17, 2023
PubMed

Insights

Cyclin-dependent kinase 7 inhibition causes cancer cells to permanently exit the cell cycle. Enhanced mammalian target of rapamycin (mTOR) signaling, not DNA damage, drives this sensitivity, explaining why some cancers respond better to this therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Tumor growth relies on cellular proliferation.
  • Cyclin-dependent kinase 7 (CDK7) is a therapeutic target due to its role in cell cycle regulation and gene expression.
  • The basis for cancer cell sensitivity to CDK7 inhibition (CDK7i) is not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms underlying cancer cell sensitivity to CDK7 inhibition.
  • To identify factors that predict response to CDK7i therapies.

Main Methods:

  • Utilized samuraciclib, a CDK7 inhibitor.
  • Performed a genome-wide CRISPR knockout screen to identify genetic modifiers of sensitivity.
  • Assessed cell-cycle progression, DNA damage signaling, and cell death.
  • Investigated the role of mammalian target of rapamycin (mTOR) signaling pathways.
  • Analyzed sensitivity in cancer cell lines with varying PIK3CA mutation status.

Main Results:

  • CDK7 inhibition by samuraciclib induces permanent cell-cycle exit (senescence) without triggering DNA damage or cell death.
  • Active mTOR signaling was identified as a key promoter of samuraciclib-induced senescence.
  • Inhibition of mTOR reduced sensitivity to samuraciclib.
  • Increased mTOR-dependent growth signaling correlated with heightened sensitivity to CDK7i.
  • Restoring wild-type PIK3CA in cells with growth-promoting mutations decreased sensitivity to CDK7i.

Conclusions:

  • Enhanced cellular growth signaling, particularly via mTOR, is sufficient to confer sensitivity to CDK7 inhibition.
  • This finding explains differential sensitivity of various cancer types to CDK7 inhibitors.
  • Targeting CDK7 offers a promising therapeutic strategy for cancers with high growth signaling.
Keywords:
CDK inhibitionCDK7 inhibitorcancer treatmentcell cyclecell sizecell-cycle arrestcellular growthmTOR singalingproliferationsamuraciclibsenescence

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