FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer

Related Experiment Video

Updated: Jun 22, 2025

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells
15:53

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells

Published on: August 21, 2013

14.9K

Yifan Tai1,2, Angela Chow1, Seoyoung Han1,3

  • 1Institute for Cancer Genetics, 1130 St Nicholas Avenue, Columbia University Irving Medical Center, New York, NY, 10032, USA.

EMBO Molecular Medicine
|July 2, 2024
PubMed

Insights

Acquired resistance to PARP inhibitors (PARPi) in BRCA1/2-mutant breast cancer is a challenge. Targeting FLT1 (VEGFR1) overcomes this resistance by suppressing AKT and enhancing T-cell activity, leading to tumor regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Acquired resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) is a significant clinical challenge in BRCA1/2-mutant breast cancer.
  • Existing resistance mechanisms lack effective clinical targets, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To identify novel drivers of PARPi resistance in BRCA1/2-mutant breast cancer.
  • To investigate the therapeutic potential of targeting identified resistance mechanisms.

Main Methods:

  • Generation of in-vivo PARPi-resistant Brca1- and Bard1-mutant breast cancer models.
  • Assessment of FLT1 (VEGFR1) as a resistance driver.
  • Evaluation of FLT1 blockade effects on AKT signaling, T-cell infiltration, and tumor regression.
  • Genetic and pharmacological targeting of Flt1 in resistant models.
  • Retrospective analysis of patient data correlating FLT1 activation with progression-free survival.

Main Results:

  • FLT1 (VEGFR1) was identified as a key driver of PARPi resistance through novel non-canonical signaling pathways.
  • FLT1 blockade suppressed AKT activation and increased CD8+ T-cell infiltration.
  • Targeting Flt1, genetically or pharmacologically (axitinib), re-sensitized resistant tumors to PARPi, leading to dramatic regression.
  • Pre-treatment FLT1 activation in patients correlated with shorter progression-free survival.

Conclusions:

  • FLT1 (VEGFR1) represents a novel therapeutic target for overcoming PARPi resistance in BRCA1/2-mutant breast cancer.
  • FLT1 blockade offers a promising strategy to re-sensitize tumors to PARPi via immune-mediated and cell-intrinsic mechanisms.
Keywords:
Breast CancerFLT1PARP-Inhibitor-ResistanceVEGFR1

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