【原】中国学者对三阴性乳腺癌代谢分型施策

SIBCS 2020-11-12

展开全文

　　三阴性乳腺癌是雌激素、孕激素、HER2三大受体均为阴性的一类恶性肿瘤，故对传统内分泌治疗和HER2靶向治疗不敏感，亟需进一步分型施策，寻找其他靶向治疗方法。众所周知，肿瘤细胞与正常细胞相比，需要大量的营养和能量以维持快速增殖，故代谢特征显著不同。目前已有许多不同类型的代谢抑制剂已被研发，可针对肿瘤细胞的不同代谢特征进行治疗，不过这些药物的疗效大多不尽人意。其中最大的问题即不同种类肿瘤或同一种类肿瘤不同亚型的代谢特征显著不同。从肿瘤代谢的角度，对三阴性乳腺癌进行区分，有助于发现三阴性乳腺癌的特殊靶点，进而优化三阴性乳腺癌的精准靶向治疗。

　　2020年11月11日，美国《细胞》旗下《细胞代谢》在线发表复旦大学附属肿瘤医院龚悦、吉芃、杨云松、余天剑、肖毅、金明亮、马丁、国琳玮、裴雨晨、柴文君、李大强、胡欣、江一舟、邵志敏、复旦大学附属儿科医院谢韶、北京大学生命科学学院生物医学前沿创新中心白凡、法国马赛大学癌症研究中心弗朗索瓦·贝图奇等学者的研究报告，对三阴性乳腺癌的代谢途径进行深入分型分析，揭示了潜在的代谢治疗靶点。

　　该研究首先利用目前全球样本量最大的复旦大学附属肿瘤医院三阴性乳腺癌多组学（基因、转录、代谢、临床）数据库，对465例三阴性乳腺癌患者的代谢异常进行分析，根据代谢特征将三阴性乳腺癌进一步分为三种代谢途径亚型：

MPS1：脂质合成亚型（脂肪代谢上调）
MPS2：糖酵解亚型（碳水化合物和核苷酸代谢上调）
MPS3：混合亚型（上述代谢途径部分失调）

　　随后，对72例三阴性乳腺癌样本的代谢组学特征进行分析验证，结果发现上述三种亚型具有不同的预后、分子亚型分布和基因组变化：

MPS1：脂质合成型（大多由管腔雄激素受体型三阴性乳腺癌组成）对脂肪酸合成抑制剂较敏感
MPS2：糖酵解亚型（较多由基底样免疫抑制型三阴性乳腺癌组成）对糖酵解途径抑制剂较敏感，尤其乳酸脱氢酶（LDH）抑制剂可显著提高免疫检查点PD1抑制剂免疫疗法的敏感性。

　　因此，该研究结果表明，三阴性乳腺癌的代谢特征各不相同，针对不同的肿瘤代谢特征，可开发不同的个体化靶向治疗，进行分型施策。

相关链接

Cell Metab. 2020 Nov 11:33(1):1-14.

Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets.

Yue Gong, Peng Ji, Yun-Song Yang, Shao Xie, Tian-Jian Yu, Yi Xiao, Ming-Liang Jin, Ding Ma, Lin-Wei Guo, Yu-Chen Pei, Wen-Jun Chai, Da-Qiang Li, Fan Bai, Francois Bertucci, Xin Hu, Yi-Zhou Jiang, Zhi-Ming Shao.

Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China; Biomedical Pioneering Innovation Center, School of Life Sciences, Peking University, Beijing, China; Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France; Children's Hospital, Fudan University, Shanghai, China.

HIGHLIGHTS

The metabolic reprogramming and heterogeneity of TNBC is systematically characterized
TNBCs are classified into three subtypes on the basis of metabolic pathways
Three subtypes show distinct sensitivities to various metabolic inhibitors
Inhibition of LDH enhances tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs

Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.

KEYWORDS: triple-negative breast cancer; metabolism; heterogeneity; metabolic pathway; subtype; glycolysis; metabolic inhibitor; immunotherapy; survival

DOI: 10.1016/j.cmet.2020.10.012