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Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs

Author

Listed:
  • Nisebita Sahu

    (Genentech)

  • Jean-Philippe Stephan

    (Genentech
    Present address: Models and HTS Department, Institut de Recherche SERVIER, 125 Chemin de Ronde, 78290 Croissy-Sur-Seine, France)

  • Darlene Dela Cruz

    (Genentech)

  • Mark Merchant

    (Genentech)

  • Benjamin Haley

    (Genentech)

  • Richard Bourgon

    (Genentech)

  • Marie Classon

    (Genentech)

  • Jeff Settleman

    (Genentech
    Present address: Calico Life Sciences, 1170 Veterans Boulevard, South San Francisco, California 94080, USA)

Abstract

Acquired resistance to cancer drug therapies almost always occurs in advanced-stage patients even following a significant response to treatment. In addition to mutational mechanisms, various non-mutational resistance mechanisms have now been recognized. We previously described a chromatin-mediated subpopulation of reversibly drug-tolerant persisters that is dynamically maintained within a wide variety of tumour cell populations. Here we explore a potential role for microRNAs in such transient drug tolerance. Functional screening of 879 human microRNAs reveals miR-371-3p as a potent suppressor of drug tolerance. We identify PRDX6 (peroxiredoxin 6) as a key target of miR-371-3p in establishing drug tolerance by regulating PLA2/PKCα activity and reactive oxygen species. PRDX6 expression is associated with poor prognosis in cancers of multiple tissue origins. These findings implicate miR-371-3p as a suppressor of PRDX6 and suggest that co-targeting of peroxiredoxin 6 or modulating miR-371-3p expression together with targeted cancer therapies may delay or prevent acquired drug resistance.

Suggested Citation

  • Nisebita Sahu & Jean-Philippe Stephan & Darlene Dela Cruz & Mark Merchant & Benjamin Haley & Richard Bourgon & Marie Classon & Jeff Settleman, 2016. "Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12351
    DOI: 10.1038/ncomms12351
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