三陰性乳腺癌是雌激素、孕激素、HER2三大受體均為陰性的一類惡性腫瘤，故對傳統(tǒng)內(nèi)分泌治療和HER2靶向治療不敏感，亟需進(jìn)一步分型施策，尋找其他靶向治療方法。眾所周知，腫瘤細(xì)胞與正常細(xì)胞相比，需要大量的營養(yǎng)和能量以維持快速增殖，故代謝特征顯著不同。目前已有許多不同類型的代謝抑制劑已被研發(fā)，可針對腫瘤細(xì)胞的不同代謝特征進(jìn)行治療，不過這些藥物的療效大多不盡人意。其中最大的問題即不同種類腫瘤或同一種類腫瘤不同亞型的代謝特征顯著不同。從腫瘤代謝的角度，對三陰性乳腺癌進(jìn)行區(qū)分，有助于發(fā)現(xiàn)三陰性乳腺癌的特殊靶點，進(jìn)而優(yōu)化三陰性乳腺癌的精準(zhǔn)靶向治療。
2020年11月11日，美國《細(xì)胞》旗下《細(xì)胞代謝》在線發(fā)表復(fù)旦大學(xué)附屬腫瘤醫(yī)院龔悅、吉芃、楊云松、余天劍、肖毅、金明亮、馬丁、國琳瑋、裴雨晨、柴文君、李大強、胡欣、江一舟、邵志敏、復(fù)旦大學(xué)附屬兒科醫(yī)院謝韶、北京大學(xué)生命科學(xué)學(xué)院生物醫(yī)學(xué)前沿創(chuàng)新中心白凡、法國馬賽大學(xué)癌癥研究中心弗朗索瓦·貝圖奇等學(xué)者的研究報告，對三陰性乳腺癌的代謝途徑進(jìn)行深入分型分析，揭示了潛在的代謝治療靶點。
該研究首先利用目前全球樣本量最大的復(fù)旦大學(xué)附屬腫瘤醫(yī)院三陰性乳腺癌多組學(xué)（基因、轉(zhuǎn)錄、代謝、臨床）數(shù)據(jù)庫，對465例三陰性乳腺癌患者的代謝異常進(jìn)行分析，根據(jù)代謝特征將三陰性乳腺癌進(jìn)一步分為三種代謝途徑亞型：
MPS1：脂質(zhì)合成亞型（脂肪代謝上調(diào)）
MPS2：糖酵解亞型（碳水化合物和核苷酸代謝上調(diào)）
MPS3：混合亞型（上述代謝途徑部分失調(diào)）
隨后，對72例三陰性乳腺癌樣本的代謝組學(xué)特征進(jìn)行分析驗證，結(jié)果發(fā)現(xiàn)上述三種亞型具有不同的預(yù)后、分子亞型分布和基因組變化：
MPS1：脂質(zhì)合成型（大多由管腔雄激素受體型三陰性乳腺癌組成）對脂肪酸合成抑制劑較敏感
MPS2：糖酵解亞型（較多由基底樣免疫抑制型三陰性乳腺癌組成）對糖酵解途徑抑制劑較敏感，尤其乳酸脫氫酶（LDH）抑制劑可顯著提高免疫檢查點PD1抑制劑免疫療法的敏感性。
因此，該研究結(jié)果表明，三陰性乳腺癌的代謝特征各不相同，針對不同的腫瘤代謝特征，可開發(fā)不同的個體化靶向治療，進(jìn)行分型施策。
相關(guān)鏈接
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
