Your browser doesn't support javascript.
loading
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.
Afiliación
  • Echeverria GV; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Ge Z; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Seth S; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Zhang X; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Jeter-Jones S; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Zhou X; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Cai S; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Tu Y; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • McCoy A; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Peoples M; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Sun Y; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Qiu H; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chang Q; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Bristow C; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Carugo A; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Shao J; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Ma X; Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA.
  • Harris A; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Mundi P; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lau R; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Ramamoorthy V; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wu Y; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Alvarez MJ; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Califano A; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Moulder SL; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Symmans WF; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Marszalek JR; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Heffernan TP; Center for Co-Clinical Trials Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chang JT; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • Piwnica-Worms H; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Transl Med ; 11(488)2019 04 17.
Article en En | MEDLINE | ID: mdl-30996079
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.
Asunto(s)
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Doxorrubicina / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Doxorrubicina / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos