PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER⁺ breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized ¹³C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[¹⁸F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.

编码PI3Kα亚型的PIK3CA是雌激素受体（ER）阳性乳腺癌中最常见的致癌基因。临床上使用同种型选择性PI3K抑制剂，但固有的和获得性耐药性限制了它们的实用性。受益于这些药物的患者的更好选择需要可预测的生物标志物。我们在这里显示，药物治疗后持续的FOXM1表达是对ER ⁺乳腺癌中PI3Kα抑制的抗性的生物标记。FOXM1驱动乳酸脱氢酶（LDH）的表达，而不驱动己糖激酶2（HK-II）的表达。因此，可以使用LDH催化的超极化^13的MRI检测下游的代谢变化丙酮酸和乳酸之间的C标签交换，而不是通过HK-II介导的葡萄糖类似物2-脱氧-2- [ ¹⁸ F]氟脱氧葡萄糖的正电子发射断层扫描测量。使用这种成像方法对乳腺癌的治疗反应进行快速评估，可以帮助确定受益于PI3Kα抑制作用的患者，并设计药物组合以抵消耐药性的出现。