由于三阴性乳腺癌对内分泌治疗和抗HER2治疗无效，故通常必须接受化疗，其中包括手术切除肿瘤之前的新辅助化疗。不幸的是，不少患者对新辅助化疗耐药。三阴性乳腺癌新辅助化疗耐药是亟待解决的临床难题。
2019年4月17日，美国科学促进会《科学》旗下《转化医学》在线发表德克萨斯大学MD安德森癌症中心、德克萨斯大学健康科学中心、纽约哥伦比亚大学医疗中心、纽约达尔文医疗的研究报告，利用三阴性乳腺癌治疗前患者来源异种移植模型、三阴性乳腺癌新辅助化疗患者连续活检标本，探讨了三阴性乳腺癌新辅助化疗的耐药机制。
该研究通过患者来源异种移植肿瘤基因组测序和肿瘤细胞条码技术克隆追踪发现，多柔比星（阿霉素）联合环磷酰胺标准方案早期化疗后，残余肿瘤仍然保留治疗前肿瘤的亚克隆结构，不过其转录组、蛋白质组、组织学特征不同于治疗前肿瘤。一旦治疗停止，残余肿瘤产生对多柔比星＋环磷酰胺敏感的肿瘤，其转录组、蛋白质组、组织学特征与治疗前肿瘤相似，证明肿瘤能够处于可逆耐药状态，其不涉及多柔比星＋环磷酰胺耐药克隆选择机制。三阴性乳腺癌新辅助化疗患者连续活检标本可见类似的组织学变化和保持稳定的亚克隆结构，证实多柔比星＋环磷酰胺新辅助化疗患者来源异种移植肿瘤具有人类三阴性乳腺癌化疗耐药分子特征。最后，利用目前处于一期临床研发的线粒体代谢靶向药物氧化磷酸化抑制剂，针对三阴性乳腺癌的弱点进行药物抑制，可以延长了残余肿瘤再生复发时间。
因此，该研究结果表明，非选择机制引起三阴性乳腺癌对多柔比星＋环磷酰胺新辅助化疗耐药，其可逆耐药状态可被线粒体代谢靶向药物氧化磷酸化抑制剂逆转。
Sci Transl Med. 2019 Apr 17;11(488):eaav0936.
Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state.
Gloria V. Echeverria, Zhongqi Ge, Sahil Seth, Xiaomei Zhang, Sabrina Jeter-Jones, Xinhui Zhou, Shirong Cai, Yizheng Tu, Aaron McCoy, Michael Peoples, Yuting Sun, Huan Qiu, Qing Chang, Christopher Bristow, Alessandro Carugo, Jiansu Shao, Xiaoyan Ma, Angela Harris, Prabhjot Mundi, Rosanna Lau, Vandhana Ramamoorthy, Yun Wu, Mariano J. Alvarez, Andrea Califano, Stacy L. Moulder, William F. Symmans, Joseph R. Marszalek, Timothy P. Heffernan, Jeffrey T. Chang, Helen Piwnica-Worms.
University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Texas Health Science Center, Houston, TX 77030, USA; Columbia University Medical Center, New York, NY 10032, USA; DarwinHealth Inc., New York, NY 10018, USA.
Metabolizing cancer chemoresistance: Triple-negative breast cancer is an aggressive malignancy that is not susceptible to hormone inhibition and must therefore be treated with conventional chemotherapy. This includes neoadjuvant chemotherapy, where the treatment is initiated before surgical resection, but unfortunately, patients develop resistance to this intervention, which makes it difficult to fully eradicate their tumors. By tracking individual tumor cell clones and analyzing the genomics of patient-derived xenografts, Echeverria et al. found that this resistance to neoadjuvant therapy can be mediated by a reversible mechanism targetable by a pharmacological inhibitor of mitochondrial metabolism.
Eradicating triple-negative breast cancer (TNBC) resistant to neoadjuvant chemotherapy (NACT) is a critical unmet clinical need. In this study, patient-derived xenograft (PDX) models of treatment-naive TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after treatment with standard frontline chemotherapies, doxorubicin (Adriamycin) combined with cyclophosphamide (AC), maintained the subclonal architecture of untreated tumors, yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to AC-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as an AC resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes and maintenance of stable subclonal architecture, demonstrating that AC-treated PDXs capture molecular features characteristic of human TNBC chemoresistance. Last, pharmacologic inhibition of oxidative phosphorylation using an inhibitor currently in phase 1 clinical development delayed residual tumor regrowth. Thus, AC resistance in treatment-naive TNBC can be mediated by nonselective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities.
DOI: 10.1126/scitranslmed.aav0936
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