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Cancer Drug Response Linked to Transcript Isoform Markers

NEW YORK (GenomeWeb) – A Canadian research team has garnered new evidence supporting the notion that the expression of certain transcript isoforms might offer clues to cancer drug response.

The researchers used a new meta-analysis framework to search for splicing isoforms tied to drug response in cell lines assessed for two large pharmacogenomic studies, and looking at more than a dozen cancer drugs. The results, appearing online today in Nature Communications, identified individual transcript isoforms that corresponded to breast cancer cell response to lapatinib, erlotinib, AZD6244, and paclitaxel.

"We validated four isoform-based biomarkers predictive of responses to lapatinib, erlotinib, AZD6244 (MEK inhibitor), and paclitaxel, indicating that isoforms constitute a promising new class of biomarkers for cytotoxic and targeted anticancer therapies," corresponding author Benjamin Haibe-Kains, a researcher affiliated with the Princess Margaret Cancer Centre, the University of Toronto, and the Ontario Institute of Cancer Research, and his co-authors wrote.

The team's analysis centered on data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) and the Genomics of Drug Sensitivity in Cancer (GDSC) from the Wellcome Trust Sanger Institute and the Massachusetts General Hospital Cancer Center. By bringing together pan-cancer RNA sequence profiles for more than 1,800 cancer cell lines characterized in these pharmacogenomic collections, the group got a look at potential isoform markers for response to 15 cancer drugs.

They subsequently attempted to verify potential biomarkers for cancer cell line drug responses in general using data from the Roche Genentech Cell Line Screening Initiative. Their breast cancer-focused analysis led to possible gene splice markers that they went on to test in a breast cancer dataset described in a Genome Biology study in 2013 and University Health Network genomic data set profiled for an analysis in Cell last year.

The meta-analysis pipeline used for the study led to a "wide range of statistically significant biomarkers for each drug," the authors wrote, noting that "there were significantly more isoform-based biomarkers than gene expression and copy number alterations and their concordance index was superior."

After the validation stage of the study, the researchers were left with an IGF2BP2 splicing isoform associated with breast cancer response to AZD6244, along with NECTIN4 and ITGB6 isoforms linked to lapatinib and erlotinib response in breast cancer, respectively. On the other hand, lack of response to paclitaxel was more common in the presence of a KLHDC9 isoform.

Still other splicing variations seemed to spell better or worse drug responses in the pan-cancer cell line collection. Even so, they cautioned that mutation-based biomarkers showed closer ties to cancer cell line responses to a small handful of drugs, including the ALK and ROS1 inhibitor crizotinib and the tyrosine kinase inhibitor nilotinib. 

"The advent of RNA sequencing technology enables efficient quantification of alternatively spliced transcripts in cancer cells," Haibe-Kains and his colleagues wrote. "Our genome-wide search for biomarkers demonstrates that gene isoforms constitute a rich resource of transcriptomic features associated with response to targeted and chemotherapies in vitro."