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A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

Michalis Mastri1, Amanda Tracz1, Christina R Lee2

  • 1Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Cell Reports
|December 28, 2018
PubMed

Insights

Stopping VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) therapy can cause rebound tumor growth due to senescence-associated secretory phenotypes (SASPs). Blocking SASP regulators may improve outcomes after VEGFR TKI treatment failure.

Area of Science:

  • Oncology
  • Cellular Biology
  • Cancer Therapeutics

Background:

  • VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) are used to treat various cancers.
  • Preclinical studies suggest VEGFR TKIs can paradoxically promote metastatic disease.
  • Cessation of VEGFR TKI treatment after resistance can lead to tumor rebound.

Purpose of the Study:

  • To investigate the mechanisms driving tumor rebound after VEGFR TKI withdrawal.
  • To explore the role of senescence-associated secretory phenotypes (SASPs) in this rebound phenomenon.
  • To identify potential therapeutic strategies to mitigate rebound tumor growth.

Main Methods:

  • Preclinical cancer models were used to study tumor response to VEGFR TKI treatment and withdrawal.
  • Analysis of cellular changes, including senescence hallmarks and secretome composition.
  • Investigated the effect of blocking SASP regulators (mTOR, IL-6) on tumor rebound.
  • Assessed the reversibility of senescence and tumor growth after prolonged drug withdrawal.

Main Results:

  • Tumor rebound after VEGFR TKI withdrawal was associated with SASP-mimicking secretomes (ATIS).
  • Blockade of SASP regulators like mTOR and IL-6 partially inhibited rebound tumor growth.
  • Senescence hallmarks and tumor growth were reversible after extended drug withdrawal periods.
  • These findings suggest the hijacking of SASP machinery is transient.

Conclusions:

  • VEGFR TKI withdrawal can induce transient, senescence-like states that promote tumor rebound.
  • Targeting SASP regulators may offer a strategy to improve outcomes in patients experiencing VEGFR TKI failure.
  • Senescence-targeted therapies (senotherapeutics) warrant further investigation for post-VEGFR TKI treatment.
Keywords:
IL-6SASPVEGF RTKIantiangiogenic therapymTORmetastasisreboundresistancesecretomesenescence

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