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Potentially Protective MicroRNA Uncovered in Screen for Targeted Cancer Drug Resistance

NEW YORK (GenomeWeb) – A study appearing online this week in Nature Communications suggests that a microRNA called miR-371-3p can suppress drug tolerance in tumor cells from advanced cancer patients.

In the hopes of tracking down miRNA contributors to acquired drug resistance, researchers from Genentech did a functional screen focused on nearly 900 human miRNAs. The search led to miR-371-3p, which they subsequently found to be a regulator of the peroxiredoxin 6 gene PRDX6 — a phospholipase signaling and oxidative stress-related gene with higher-than-usual expression in tumors from aggressive cancer with relatively poor outcomes.

"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," senior author Jeff Settleman, a researcher with Genentech's discovery oncology department, and his co-authors wrote.

Even as new drug resistance-related mutations are being identified in various cancers, the team noted, there is growing evidence that non-mutational mechanisms such as epigenetic features may play a role in acquired resistance or reversible drug tolerance.

"Drug-tolerant persisters constitute a subpopulation of tumor cells that emerge at relatively high frequency upon treatment of largely drug-sensitive cancer cell populations with various anti-cancer agents," the researchers wrote, noting that "miRNAs may … regulate genes required to engage the [drug-tolerant persister] state.

Using a library of miRNA mimics representing 879 human miRNA precursors, the team did a drug response screen in a PC9 non-small cell lung cancer cell line exposed to the EGFR kinase inhibitor erlotinib (sold by Genentech as Tarceva). It also looked at the consequences of introducing 885 miRNA inhibitors.

More than half of the miRNA inhibitors led to higher-than-usual numbers of drug-tolerant cells, with just two anti-miRs decreasing the apparent drug tolerance.

On the other hand, 39 of the miRNAs that did not have obvious effects on untreated cells seemed to dial down the number of drug-tolerant persister cells following erlotinib exposure. That effect was most pronounced for the pre-miRNA pre-miR-371, which leads to both miR-371-3p and miR-371-5p.

The researchers focused in on one of these, miR-371-3p, which showed diminished expression in drug-tolerant persister cells. Through a series of follow-up analyses — including over-expression, gene knockdown, and mouse xenograft experiments, they found that the miRNA targets PRDX6, PLC-beta4, and STX12, genes involved in phospholipase signaling.

In particular, the team reported that enhanced expression of miR-371 seemed to dial down xenograft tumor growth, drug tolerance, and relapse in erlotinib-treated mice, while the expression of PRDX6 and other miR-371 targets were up-regulated in other mouse tumors. Similarly, a search of data from the Cancer Genome Atlas suggested PRDX6 expression may also be ramped up in multiple human cancer types.

Together, the study's authors said, the results "reveal a major regulatory role for miRNAs in the emergence of reversible drug tolerance and suggest that combining current targeted therapies with inhibitors of [phospholipase signaling and reactive oxygen species] accumulation could provide a treatment strategy to delay some types of drug resistance in human cancer."