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Br J Cancer. 2018 Apr;118(7):985-994. doi: 10.1038/s41416-018-0014-0. Epub 2018 Mar 8.

AKR1C enzymes sustain therapy resistance in paediatric T-ALL.

Author information

1
Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.
2
Istituto di Ricerca paediatrica Città della Speranza-IRP, corso Stati Uniti 4, Padova, 35127, Italy.
3
Clinic of paediatric Oncohematology, University Hospital of Padova, Padova, 35128, Italy.
4
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, 35128, Italy.
5
Istituto Oncologico Veneto - IRCCS, Padova, 35128, Italy.
6
Department of paediatric, Centro Ricerca M. Tettamanti, University of Milano Bicocca, Fondazione MBBM, Monza, 20900, Italy.
7
Istituto di Ricerca paediatrica Città della Speranza-IRP, corso Stati Uniti 4, Padova, 35127, Italy. luca.persano@unipd.it.

Abstract

BACKGROUND:

Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.

METHODS:

Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.

RESULTS:

We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.

CONCLUSIONS:

Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy.

PMID:
29515258
PMCID:
PMC5931104
DOI:
10.1038/s41416-018-0014-0
[Indexed for MEDLINE]
Free PMC Article

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