Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Invest New Drugs. 2018 Aug;36(4):657-666. doi: 10.1007/s10637-018-0585-x. Epub 2018 Apr 2.
Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.
雷帕霉素哺乳动物靶点复合物 1（mTORC1）抑制剂可增强急性髓系白血病（AML）细胞体外化疗反应。然而，抑制 mTORC1 是否能增强 AML 化疗的临床反应仍存在争议。我们之前使用甲醛固定全血或骨髓标本的磷酸化特异性流式细胞术对临床试验中的 AML 原始细胞中 mTORC1 的激酶活性进行了优化测量。为了验证 mTORC1 作为 AML 的治疗靶点，我们在复发性、难治性或未经治疗的高危 AML 患者中进行了两项临床试验，将 mTORC1 抑制剂（西罗莫司）与 MEC（米托蒽醌、依托泊苷、阿糖胞苷）联合使用。
在西罗莫司治疗前后进行核糖体蛋白 S6 磷酸化（pS6）的流式细胞术测量，以确定 mTORC1 抑制是否富集化疗反应。
在 51 例可评估的患者中，联合方案的总体反应率（ORR）为 47%（95%置信区间 33-61%，33%CR，2%CRi，12%PR），毒性与单独使用 MEC 的历史经验相似。37 例患者在接受西罗莫司治疗前进行了基线 pS6 测量，其中 27 例（73%）表现出 mTORC1 活性。有基线 mTORC1 活性和无基线 mTORC1 活性的患者之间的 ORR 无显著差异（分别为 52%和 40%，p=0.20）。在基线时靶激活且治疗期间抑制 mTORC1 的患者中，ORR 为 71%（12/17），而无靶抑制的患者中为 20%（2/10）。
流式细胞术固定全血 pS6 可能是预测 mTORC1 抑制剂方案临床反应的生物标志物。这些数据为临床证实 mTORC1 激活介导 AML 患者的化疗耐药提供了证据。
