| Autor: |
Tai, Yifan, Chow, Angela, Han, Seoyoung, Coker, Courtney, Ma, Wanchao, Gu, Yifan, Estrada Navarro, Valeria, Kandpal, Manoj, Hibshoosh, Hanina, Kalinsky, Kevin, Manova-Todorova, Katia, Safonov, Anton, Walsh, Elaine M, Robson, Mark, Norton, Larry, Baer, Richard, Merghoub, Taha, Biswas, Anup K, Acharyya, Swarnali |
| Zdroj: |
EMBO Molecular Medicine; Aug2024, Vol. 16 Issue 8, p1957-1980, 24p |
| Abstrakt: |
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. Synopsis: PARP inhibitor (PARPi) resistance is a major treatment challenge that dramatically shortens patient survival. Using new mouse models of PARPi response and recurrence, we identified FLT1 as a potential biomarker and therapeutic target for reversing PARPi resistance in BRCA-mutant breast cancer. New mouse models were developed that recapitulate the PARPi response and recurrence observed in patients. A novel PARPi-adaptive resistance mechanism driven by the PGF-FLT1-AKT pathway was identified. FLT1 signaling protected the cells from PARPi-induced death by activating AKT pro-survival pathways and by dampening the cytotoxic immune response. Blocking FLT1 signaling, either genetically or pharmacologically using axitinib, re-sensitized PARPi-resistant tumors to PARPi treatment in mice. High FLT1 activation in tumor cells at pre-treatment significantly correlated with shorter progression-free survival on PARPi in patients with breast cancer. PARP inhibitor (PARPi) resistance is a major treatment challenge that dramatically shortens patient survival. Using new mouse models of PARPi response and recurrence, we identified FLT1 as a potential biomarker and therapeutic target for reversing PARPi resistance in BRCA-mutant breast cancer. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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