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Dec 6, 2011

KRAS Variant Linked with Therapy Resistance in Epithelial Ovarian Cancer

  • Screening for a known variant in the KRAS oncogene can help predict whether patients with  epithelial ovarian cancer (EOC) are likely to be resistant to platinum-based chemotherapy, scientists claim. An international team of researchers led by Yale University found that postmenopausal women (aged over 52 years) with EOC who carry the KRAS-variant and wild-type BRCA genes survived about half as long as women without the variant.

    This decrease in survival was subsequently found to be linked with increased resistance of KRAS-variant cancers to both first-line platinum-based agent, and those used in second-line therapy. Joanne B. Weidhaas, M.D., and colleagues, report their findings in Oncogene in a paper titled “A KRAS-variant is a Biomarker of Poor Outcome, Platinum Chemotherapy Resistance and a Potential Target for Therapy in Ovarian Cancer.”

    Previous research has demonstrated that miRNA expression patterns are linked with EOC pathogenesis, patient outcome, response to treatment, and chemotherapy and platinum resistance. Inherited SNPs that disrupt miRNA coding sequences and miRNA binding sites in the 3’ untranslated regions (3’UTR) of oncogenes have also been discovered, the team continues.

    One of these functional variants, the KRAS-variant (rs61764370) is sited in the KRAS 3’UTR in a let-7 miRNA complementary site and has been identified as a marker for the risk of a variety of cancers. The KRAS variant has in addition been linked with altered miRNA and gene expression in a range of tumors, identified as a biomarker of resistance to targeted chemotherapy in colon cancer. 

    To investigate whether the KRAS-variant is associated with overall survival in EOC, the team evaluated 454 EOC patients who were either known to be negative for deleterious BRCA mutations or who hadn’t been tested for BRCA. The results suggested that the KRAS-variant was specifically associated with reduced survival in postmenopausal women (over the age of 52 years).

    Median survival in non-KRAS-variant patients was 60 months, but this dropped to 34 months among patients with KRAS-variant EOC. Even when other variables were taken into account in a multivariate analysis, the KRAS-variant was a statistically significant predictor of reduced overall survival for post-menopausal EOC patients,equating to a a hazard ratio of 1.67.

    Further analyses found no association between KRAS-variant status and survival in EOC patients  of any age carrying deleterious BRCA1 or BRCA2 mutations. There were, however, too few patients to evaluate the impact of the KRAS-variant on survival in post-menopausal EOC patients harboring deleterious BRCA mutations, the authors note.  

    In the search for potential reasons why postmenopausal EOC patients with the KRAS-variant should have shorter survival, the researchers looked to see whether those carrying the SNP responded differently to platinum-based chemotherapy to those who were KRAS-variant-negative. They found that EOC patients treated using neoadjuvant platinum-containing chemotherapy followed by surgical cytoreduction were more likely to have residual disease (suboptimal cytoreduction) if they carried the KRAS variant than if they didn’t.

    In fact, 15.4% of KRAS-variant patients were suboptimally cytoreduced compared with just 3.33% of nonvariant patients. This association again held true  when other factors were controlled for using a multivariate logistic regression model.

    The link between KRAS-variant and poor response to neoadjuvant platinum-based chemotherapy was subsequently shown to be due to platinum resistance. The team found that disease recurrence within six months of receiving platinum-based chemotherapy occurred in 16.67% of KRAS-variant-positive EOC patients but just 7.56% of those who didn’t carry the SNP. 

    “The KRAS-variant was a statistically significant predictor for platinum resistance for EOC patients of all ages in a multivariate logistic regression analysis controlling for residual disease remaining after cytoreductive surgery, stage, histology, age, and grade,” the investigators state. Platinum resistance associated with KRAS-variant status also ties in with studies in BRCA mutation-carrying EOC patients, the authors note.

    “Nevertheless," the authors write, “our findings that the KRAS-variant does not predict for poor outcome in our cohort of EOC patients with known deleterious BRCA mutations may be partially explained by the fact that BRCA mutations are associated with platinum sensitivity, and this effect may act downstream of any resistance caused or exacerbated by the KRAS-variant to platinum agents."

    At the gene expression level, EOC samples taken from post-menopausal patients with the KRAS-variant displayed a upregulated signature that has previously been associated with KRAS-variant-associated triple negative breast cancer (TNBC). Overexpression of KRAS-associated downstream pathways  were also found in EOC KRAS-variant tumors, which again was similar to those found in TNBC.

    The EOC KRAS-variant gene-expression data indicated that these cancers had lower carboplatin sensitivity than non-variant EOC samples, and this was associated with notable upregulation of AKT3, which is in accord with prior research indicating that activation of the AKT pathway is frequently involved in platinum resistance.

    Previous studies have found that let7b miRNA is altered in KRAS -variant positive lung and triple negative breast tumors, and while miRNA expression data weren’t available for tumor samples, the team did evaluate expression of let7b miRNA in two KRAS-variant cell lines,  BG-1 and IGROV1, as well as KRAS-variant-negative tumors. This showed that let-7b was significantly lower in the cells with the KRAS-variant, supporting the investigators previous results and also a recent publication demonstrating an association between low levels of the miRNA and poor ovarian cancer outcomes.

    They then tested the sensitivity of a range of EOC cell lines to different chemotherapeutic drugs. The results showed that the KRAS-variant positive/BRCA wild-type cell line BG1 was notably resistant to carboplatin and carboplatin/paclitaxel combination therapy when compared with CAOV3, a KRAS-variant-negative/BRCA wild-type cell line. In comparison, the IGROV1 cell line, which also carries the KRAS-variant and a deleterious BRCA1 mutation, wasn’t resistant to the same chemotherapy agents when compared with CAOV3. The BG1 cell line was also resistant to commonly used second-line therapeutic agents including doxorubicin, topotecan, and gemcitabine.

    Finally, the investigators showed that targeting the KRAS-variant transcript in the BG1 cell line using siRNA/miRNA-like complexes led to a significant decrease in cell survival and a decrease in KRAS protein levels. The two nonvariant EOC cell lines CAOV3 adn SKOV3 weren’t affected by the targeting oligonucleotide duplexes and demonstrated no decreased in KRAS protein levels.

    “There is still work to be done to better define the mechanisms of KRAS-variant associated platinum resistance and its potential as a future target for therapy in EOC,” the authors conclude. However, the finding that direct targeting of the KRAS-variant lesion in EOC cell lines leads to enhanced cell death is particularly relevant.

    “While there is considerable work to be done to understand the mechanisms behind these findings, they do suggest continued critical dependence of these tumors on this single, noncoding germ-line lesion," the scientists state. "While there has been a significant effort to tailor cancer treatment by measuring tumor gene expression and determining tumor acquired mutations, there are few, if any, germ-line variants that have previously been shown to be critical targets for therapy in cancer.”


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