Research ArticleCancer

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

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Science Translational Medicine  17 Apr 2019:
Vol. 11, Issue 488, eaav0936
DOI: 10.1126/scitranslmed.aav0936

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Metabolizing cancer chemoresistance

Triple-negative breast cancer is an aggressive malignancy that is not susceptible to hormone inhibition and must therefore be treated with conventional chemotherapy. This includes neoadjuvant chemotherapy, where the treatment is initiated before surgical resection, but unfortunately, patients develop resistance to this intervention, which makes it difficult to fully eradicate their tumors. By tracking individual tumor cell clones and analyzing the genomics of patient-derived xenografts, Echeverria et al. found that this resistance to neoadjuvant therapy can be mediated by a reversible mechanism targetable by a pharmacological inhibitor of mitochondrial metabolism.

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.

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