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

doi:10.1126/scitranslmed.aav0936

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

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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-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 language	English (US)
Article number	eaav0936
Journal	Science translational medicine
Volume	11
Issue number	488
DOIs	https://doi.org/10.1126/scitranslmed.aav0936
State	Published - Apr 17 2019

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General Medicine

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Advanced Technology Genomics Core
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Functional Proteomics Reverse Phase Protein Array Core
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10.1126/scitranslmed.aav0936

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Echeverria, G. V., 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., ... Piwnica-Worms, H. (2019). Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Science translational medicine, 11(488), Article eaav0936. https://doi.org/10.1126/scitranslmed.aav0936

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

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title = "Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state",

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.",

author = "Echeverria, {Gloria V.} and Zhongqi Ge and Sahil Seth and Xiaomei Zhang and Sabrina Jeter-Jones and Xinhui Zhou and Shirong Cai and Yizheng Tu and Aaron McCoy and Michael Peoples and Yuting Sun and Huan Qiu and Qing Chang and Christopher Bristow and Alessandro Carugo and Jiansu Shao and Xiaoyan Ma and Angela Harris and Prabhjot Mundi and Rosanna Lau and Vandhana Ramamoorthy and Yun Wu and Alvarez, {Mariano J.} and Andrea Califano and Moulder, {Stacy L.} and Symmans, {William F.} and Marszalek, {Joseph R.} and Heffernan, {Timothy P.} and Chang, {Jeffrey T.} and Helen Piwnica-Worms",

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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

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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Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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