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

   


Authors: Tai, Y.; Chow, A.; Han, S.; Coker, C.; Ma, W.; Gu, Y.; Estrada Navarro, V.; Kandpal, M.; Hibshoosh, H.; Kalinsky, K.; Manova-Todorova, K.; Safonov, A.; Walsh, E. M.; Robson, M.; Norton, L.; Baer, R.; Merghoub, T.; Biswas, A. K.; Acharyya, S.
Article Title: FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer
Abstract: Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer. © The Author(s) 2024.
Keywords: immunohistochemistry; signal transduction; vasculotropin; controlled study; human tissue; protein expression; gene mutation; nonhuman; cd8+ t lymphocyte; tumor associated leukocyte; biological marker; mouse; animal tissue; cell viability; dna damage; cell survival; progression free survival; ovary cancer; breast cancer; gene expression; cell infiltration; tumor volume; animal experiment; animal model; rna interference; cytotoxicity; tumor regression; angiogenesis; histology; antibiotic resistance; immune response; western blotting; immunoblotting; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; real time polymerase chain reaction; axitinib; placental growth factor; collagenase; optical density; tumor microenvironment; rna isolation; human; article; talazoparib; vegf signaling; flt1; parp-inhibitor-resistance; vegfr1
Journal Title: EMBO Molecular Medicine
Volume: 16
Issue: 8
ISSN: 1757-4676
Publisher: Wiley Blackwell  
Date Published: 2024-08-12
Start Page: 1957
End Page: 1980
Language: English
DOI: 10.1038/s44321-024-00094-2
PUBMED: 38956205
PROVIDER: scopus
PMCID: PMC11319505
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85197393328&doi=10.1038%2fs44321-024-00094-2&partnerID=40&md5=498ce295920e2a6fe1ca8c85d79163b6
Notes: Article -- Source: Scopus
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MSK Authors
  1. Larry Norton
    758 Norton
  2. Mark E Robson
    676 Robson
  3. Katia O Manova-Todorova
    161 Manova-Todorova
  4. Elaine Mary Walsh
    8 Walsh
  5. Anton Safonov
    30 Safonov
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