Resistance to neoadjuvant chemotherapy in triple negative breast cancer mediated by a reversible drug-tolerant state
| Autor: | Angela L. Harris, Timothy P. Heffernan, Prabhjot Mundi, Shirong Cai, Sabrina Jeter-Jones, Joseph R. Marszalek, Gloria V. Echeverria, Alessandro Carugo, Sahil Seth, Xiaoyan Ma, Xinhui Zhou, Huan Qiu, Yun Wu, Andrea Califano, Jeffrey T. Chang, Michael Peoples, Yizheng Tu, Yuting Sun, Mariano J. Alvarez, Stacy L. Moulder, Zhongqi Ge, Xiaomei Zhang, Jiansu Shao, Vandhana Ramamoorthy, Helen Piwnica-Worms, Aaron McCoy, Qing Chang, Christopher A. Bristow, Rosanna Lau, William Fraser Symmans |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cyclophosphamide
medicine.medical_treatment Triple Negative Breast Neoplasms Drug resistance Mice SCID Article Transcriptome Breast cancer Cell Line Tumor medicine Animals Humans Doxorubicin Neoadjuvant therapy Triple-negative breast cancer Chemotherapy business.industry General Medicine medicine.disease Xenograft Model Antitumor Assays Neoadjuvant Therapy Drug Resistance Neoplasm Cancer research Female business medicine.drug |
| Popis: | 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-naïve 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 front-line 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. Taken 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 as well as maintenance of stable subclonal architecture, demonstrating that AC-treated PDXs capture molecular features characteristic of human TNBC chemoresistance. Finally, pharmacologic inhibition of oxidative phosphorylation using an inhibitor currently in phase I clinical development delayed residual tumor regrowth. Thus, AC resistance in treatment-naïve TNBC can be mediated by non-selective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities. |
| Databáze: | OpenAIRE |
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