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.
Highlights
Acquired resistance to cancer drug therapies almost always occurs in advanced-stage patients even following a significant response to treatment
Drug-tolerant persisters (DTPs) constitute a subpopulation of tumour cells that emerge at relatively high frequency upon treatment of largely drug-sensitive cancer cell populations with various anti-cancer agents[11]
Accumulating evidence suggests a role for microRNAs in epigenetically regulating various phenotypic states in cancer cells1,2,12–18. miRNAs can impact genetic programs through post-transcriptional silencing of target genes either by promoting degradation of target messenger RNAs or by inhibiting their translation19,20. miRNAs have been implicated in regulation of various aspects of cancer biology, including drug resistance, cancer cell stemness, epithelial-to-mesenchymal transition and metastasis[19,20]
Summary
Acquired resistance to cancer drug therapies almost always occurs in advanced-stage patients even following a significant response to treatment. 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. Numerous mechanisms have been identified that contribute to drug resistance, which include both mutational (genetic) and non-mutational (presumably epigenetic) mechanisms that render tumours unresponsive to a treatment that was initially effective[9,10]. DTPs are widely observed in various cancer contexts and exhibit a reversible ability to survive otherwise lethal drug exposures, implicating epigenetic regulation[1,2,9,10]. MiRNAs have been implicated in regulation of various aspects of cancer biology, including drug resistance, cancer cell stemness, epithelial-to-mesenchymal transition and metastasis[19,20]. We hypothesize that miRNAs may regulate genes required to engage the DTP state, and test this possibility by conducting a genome-wide functional screen of miRNAs to identify those with the ability to affect the establishment of the DTP state
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