By Will Boggs MD

NEW YORK (Reuters Health) - Low expression of MSH2, a component of the mismatch-repair pathway, is associated with resistance to cisplatin treatment in bladder cancer, researchers report.

"After further follow-up and clinical validation, our hope is that MSH2-protein levels can be used as a biomarker to identify patients likely to show poor response to cisplatin-based therapy and (who) would be candidates for alternative treatments," Dr. James C. Costello of the University of Colorado Anschutz Medical Campus, in Aurora, told Reuters Health by email.

Lower MSH2 expression is associated with poorer survival in ovarian-cancer patients but not in patients with non-small-cell lung cancer. The mismatch-repair pathway has not been associated with platinum resistance in bladder cancer, but some bladder cancers have reduced or absent MSH2 expression.

Dr. Costello's team used a whole-gene CRISPR screen to investigate mediators of cisplatin resistance in bladder-cancer cells and investigated the relationship between MSH2 expression by muscle-invasive bladder cancer (MIBC) and patient outcomes.

The CRISPR screen identified three significantly platinum-resistant guide RNAs associated with MSH2, the top-ranked gene among 48 significantly resistant genes.

"From our perspective, one of the most striking results was that the genome-wide CRISPR screen resulted in all 3 of the guide RNAs for MSH2 being in the top-6 hits," Dr. Costello said. "These kinds of screening techniques can be very noisy, and we were surprised by how strong and consistent the MSH2 result was, which really pointed us in a clear direction to follow-up on MSH2."

In bladder-cancer cell lines, the loss of MSH2 resulted in 45% to 142% increases in resistance to cisplatin, the researchers report in European Urology, online November 7.

Cells with low MSH2 expression remained sensitive to oxaliplatin and other chemotherapies, indicating that MSH2 loss mediates resistance to cisplatin specifically.

In patients with bladder cancer treated with platinum-based therapy, low MSH2 protein levels were associated with significantly poorer survival, compared with patients having medium or high protein levels.

In contrast, MSH2 protein levels were not associated with survival in patients who had not received pharmacologic or radiation treatment.

Surprisingly, the researchers note, low MSH2 protein levels were not related to the tumor stage or grade.

"We would like to note that our findings are still preliminary with evaluation in a single retrospective patient cohort," Dr. Costello cautioned. "We strongly feel that the findings in our study would benefit from a future clinical trial evaluating MSH2 as a biomarker to predict the response to platinum-based chemotherapy in bladder cancer."

SOURCE: https://bit.ly/2rBuZXk

Eur Urol 2018.

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