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Horizon Discovery’s X-MAN Cell-Models Predict that a Subset of KRAS Mutated Cancers Respond to EGFR Therapy


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Horizon Discovery (Horizon) has announced the results of a clinical study published by two of its Scientific Advisory Board members, in which the Company’s X-MAN (gene-X, Mutant And Normal) cell-models were used to predict that a subset of KRAS mutated cancers respond to EGFR therapy.

The study, published by Professor Alberto Bardelli (University of Torino) and Sabine Tejpar (University of Leuven) in the Journal of The American Medical Association1 used X-MAN predictive human disease models to drive a detailed retrospective analysis of colon cancer patients who are prescribed, or excluded from Erbitux therapy based on the presence or absence of a diagnostic marker called ‘mutant KRAS’.

Specifically, the study found that patients carrying a particular and relatively common (20% of mutant KRAS cases) form of mutant KRAS (the G13D variant) are not resistant to Erbitux therapy, as previously thought. These findings therefore suggest that further analysis of specific mutant KRAS variants in prospective clinical trials are required to study the impact of specific mutant KRAS variants on Erbitux therapy.

This new study follows on from previous studies from Professor Bardelli and Tejpar published in the Journal of Cancer Research (March 2007 and February 2009) and the Journal of Clinical Oncology (October 2008), which first made the link between KRAS mutations (as well as other mutant biomarkers; BRAF and PI3K) and resistance to novel EGFR targeting colorectal cancer drugs; Erbitux and Vectibix, in up to 65% of colon cancer patients when tumor samples and response data were analyzed retrospectively.

These data were subsequently confirmed in prospective trials and it is now mandatory to test colorectal cancer patients for their KRAS status before they are prescribed these therapies; if a patient carries any mutational variant of KRAS (G12A, C, D, R, S, V or G13D) they are excluded from Erbitux therapy.

However, the findings of this new study, which used human cell lines harboring G13D or G12V mutations and DNA-sequence analysis of patient tumors, defined that while G12V mutations (28 % of KRAS mutated cases) do impart resistance to Erbitux therapy, G13D mutations (20% of KRAS mutated cases) do not.

The genetically defined and patient-relevant X-MAN human cell models used in this study were created by Professor Bardelli using Horizon’s proprietary virally-mediated gene-engineering technology called GENESIS™, which allows researchers to precisely engineer any DNA-variation into a human cell. The key feature is that these DNA-variations (in this case 7 different mutant KRAS variations) are introduced into endogenous genes, just as they occur in patients. These disease models therefore allow key questions on drug effectiveness to be addressed prior to testing in clinical trials; and informing retrospective analysis of clinical trials where possible.
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