TY - JOUR
T1 - Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state
AU - Echeverria, Gloria V.
AU - Ge, Zhongqi
AU - Seth, Sahil
AU - Zhang, Xiaomei
AU - Jeter-Jones, Sabrina
AU - Zhou, Xinhui
AU - Cai, Shirong
AU - Tu, Yizheng
AU - McCoy, Aaron
AU - Peoples, Michael
AU - Sun, Yuting
AU - Qiu, Huan
AU - Chang, Qing
AU - Bristow, Christopher
AU - Carugo, Alessandro
AU - Shao, Jiansu
AU - Ma, Xiaoyan
AU - Harris, Angela
AU - Mundi, Prabhjot
AU - Lau, Rosanna
AU - Ramamoorthy, Vandhana
AU - Wu, Yun
AU - Alvarez, Mariano J.
AU - Califano, Andrea
AU - Moulder, Stacy L.
AU - Symmans, William F.
AU - Marszalek, Joseph R.
AU - Heffernan, Timothy P.
AU - Chang, Jeffrey T.
AU - Piwnica-Worms, Helen
N1 - Publisher Copyright:
Copyright © 2019 The Authors,
PY - 2019/4/17
Y1 - 2019/4/17
N2 - 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 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-naïve TNBC can be mediated by nonselective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities.
AB - 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 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-naïve TNBC can be mediated by nonselective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities.
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U2 - 10.1126/scitranslmed.aav0936
DO - 10.1126/scitranslmed.aav0936
M3 - Article
C2 - 30996079
AN - SCOPUS:85064764089
SN - 1946-6234
VL - 11
JO - Science translational medicine
JF - Science translational medicine
IS - 488
M1 - eaav0936
ER -