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 LauVandhana 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

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbereaav0936
JournalScience Translational Medicine
Volume11
Issue number488
DOIs
StatePublished - Apr 17 2019

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Triple Negative Breast Neoplasms
Drug Therapy
Residual Neoplasm
Pharmaceutical Preparations
Neoplasms
Proteome
Transcriptome
Heterografts
Doxorubicin
Biopsy
Oxidative Phosphorylation
Therapeutics
Cyclophosphamide
Maintenance

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. / Echeverria, Gloria V.; Ge, Zhongqi; Seth, Sahil; Zhang, Xiaomei; Jeter-Jones, Sabrina; Zhou, Xinhui; Cai, Shirong; Tu, Yizheng; McCoy, Aaron; Peoples, Michael; Sun, Yuting; Qiu, Huan; Chang, Qing; Bristow, Christopher; Carugo, Alessandro; Shao, Jiansu; Ma, Xiaoyan; Harris, Angela; Mundi, Prabhjot; Lau, Rosanna; Ramamoorthy, Vandhana; Wu, Yun; Alvarez, Mariano J.; Califano, Andrea; Moulder, Stacy L.; Symmans, William F.; Marszalek, Joseph R.; Heffernan, Timothy P.; Chang, Jeffrey T.; Piwnica-Worms, Helen.

In: Science Translational Medicine, Vol. 11, No. 488, eaav0936, 17.04.2019.

Research output: Contribution to journalArticle

Echeverria, GV, Ge, Z, Seth, S, Zhang, X, Jeter-Jones, S, Zhou, X, Cai, S, Tu, Y, McCoy, A, Peoples, M, Sun, Y, Qiu, H, Chang, Q, Bristow, C, Carugo, A, Shao, J, Ma, X, Harris, A, Mundi, P, Lau, R, Ramamoorthy, V, Wu, Y, Alvarez, MJ, Califano, A, Moulder, SL, Symmans, WF, Marszalek, JR, Heffernan, TP, Chang, JT & Piwnica-Worms, H 2019, 'Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state', Science Translational Medicine, vol. 11, no. 488, eaav0936. https://doi.org/10.1126/scitranslmed.aav0936
Echeverria, Gloria V. ; Ge, Zhongqi ; Seth, Sahil ; Zhang, Xiaomei ; Jeter-Jones, Sabrina ; Zhou, Xinhui ; Cai, Shirong ; Tu, Yizheng ; McCoy, Aaron ; Peoples, Michael ; Sun, Yuting ; Qiu, Huan ; Chang, Qing ; Bristow, Christopher ; Carugo, Alessandro ; Shao, Jiansu ; Ma, Xiaoyan ; Harris, Angela ; Mundi, Prabhjot ; Lau, Rosanna ; Ramamoorthy, Vandhana ; Wu, Yun ; Alvarez, Mariano J. ; Califano, Andrea ; Moulder, Stacy L. ; Symmans, William F. ; Marszalek, Joseph R. ; Heffernan, Timothy P. ; Chang, Jeffrey T. ; Piwnica-Worms, Helen. / Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. In: Science Translational Medicine. 2019 ; Vol. 11, No. 488.
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abstract = "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-na{\"i}ve 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-na{\"i}ve TNBC can be mediated by nonselective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities.",
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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

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.

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