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.

中文翻译：

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癌细胞中的 FLT1 激活促进了乳腺癌中的 PARP 抑制剂耐药性。


对 PARP 抑制剂 （PARPi） 的获得性耐药仍然是 BRCA1/2 突变乳腺癌的治疗挑战，它大大缩短了患者的生存期。尽管已经确定了几种耐药机制，但尚未在临床上成功靶向。使用体内产生的 Brca1 和 Bard1 突变乳腺癌的新 PARPi 耐药模型，我们确定 FLT1 （VEGFR1） 是耐药的驱动因素。与 VEGF 信号转导在血管生成中的已知作用不同，我们证明了 FLT1 信号转导的一种新的非经典作用，它通过细胞内源性和细胞外源性途径的组合保护癌细胞在体内免受 PARPi 的侵害。我们证明 FLT1 阻断抑制 AKT 活化，增加 CD8+ T 细胞的肿瘤浸润，并以 T 细胞依赖性方式导致 PARPi 耐药乳腺肿瘤显着消退。此外，PARPi 耐药肿瘤细胞可以通过遗传 （Flt1 抑制） 或药理学 （axitinib） 靶向 Flt1 而很容易对 PARPi 重新敏感。重要的是，一项回顾性系列接受 PARPi 治疗的乳腺癌患者在治疗前 FLT1 激活的病例中表现出较短的无进展生存期。因此，我们的研究将 FLT1 确定为 PARPi 耐药、BRCA1/2 突变乳腺癌的潜在治疗靶点。