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

Nisebita Sahu, Jean-Philippe Stephan, Darlene Dela Cruz, Mark Merchant, Benjamin Haley, Richard Bourgon, Marie Classon and Jeff Settleman ()
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Nisebita Sahu: Genentech
Jean-Philippe Stephan: Genentech
Darlene Dela Cruz: Genentech
Mark Merchant: Genentech
Benjamin Haley: Genentech
Richard Bourgon: Genentech
Marie Classon: Genentech
Jeff Settleman: Genentech

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12351

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