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 of 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-resi

SUBMITTER: Dr. Swarnali Acharyya 

PROVIDER: S-SCDT-10_1038-S44321-024-00094-2 | biostudies-other |

REPOSITORIES: biostudies-other