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Aug 15, 2012

Gene Tied to Emergence of Chemotherapy Resistance

  • Researchers say analyzing a particular gene in high-grade serous cancer (HGSC) could help predict whether a patient’s tumor is likely to become resistant to chemotherapy over time. A team headed by researchers at the Peter MacCallum Cancer Center in Melbourne, Australia, has found that the emergence of treatment resistance in HGSC is associated with a loss or downregulation of the lipid transporter LRPB1 in the tumor.

    Peter Bowtell, Ph.D., and colleagues used SNP arrays to examine both spatial and temporal genomic variation in metastatic lesions from individual patients and 22 paired pretreatment and post-treatment tumor samples to evaluate spatial and temporal genomic variation. Spatial variation refers to the level of differential gene expression within tumor cells in the same patient at a single time point. Temporal variation provides an indication of how much genetic change occurs in the tumor over time.

    What they found was that tumors that were initially sensitive to chemotherapy but subsequently became resistant had developed more genetic changes than those that were resistant to chemotherapy from the start. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate. And when the team then either deleted or forced overexpression of the LRP1B gene in cell lines, they found that reducing LRP1B expression reduced cancer cell sensitivity to liposomal doxorubicin (but not doxorubicin), LRP1B overexpression was enough to increase the cancer cells’ sensitivity to doxorubicin.

    “We were surprised by the extent of variation that was present among the tumor deposits collected at surgery, and by how far the tumors could evolve during therapy,” Dr. Bowtell remarks. “The existence of multiple cancer genomes in an individual patient could provide many opportunities for the cancer to circumvent chemotherapy and may help explain why it has been so difficult to make progress with the disease.”

    The researchers point out that it's currently not easy to predict which women with ovarian cancer will become resistant to chemotherapy over time. “LRP1B adds to a handful of other mechanisms so far identified,” Dr. Bowtell states. “If we can comprehensively map the mechanisms that confer resistance, we may be able to predict whether some women are likely to respond to a certain drug or not, and find ways of reversing resistance. 

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