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

Author:

Tai Yifan,Chow Angela,Han Seoyoung,Coker CourtneyORCID,Ma Wanchao,Gu Yifan,Estrada Navarro ValeriaORCID,Kandpal ManojORCID,Hibshoosh Hanina,Kalinsky Kevin,Manova-Todorova KatiaORCID,Safonov Anton,Walsh Elaine M,Robson Mark,Norton Larry,Baer Richard,Merghoub Taha,Biswas Anup KORCID,Acharyya SwarnaliORCID

Abstract

AbstractAcquired 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.

Funder

U.S. Department of Defense

Irma T. Hirschl Trust

Pershing Square Sohn Cancer Research Alliance

Columbia | Irving Medical Center, Columbia University

METAvivor

American Cancer Society

Phi Beta Psi Sorority

Susan G. Komen

HHS | NIH | National Cancer Institute

Publisher

Springer Science and Business Media LLC

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