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Modelling and predicting sensitivity to targeted therapies in colorectal cancers

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Targeted therapy in colorectal cancer

A major limitation of targeted therapies for colorectal cancer is the emergence of secondary resistance. European scientists are prospectively screening for genes that mediate such acquired resistance, aiming to identify specific drug resistance biomarkers.

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Due to the complex and heterogeneous nature of cancer, the most effective treatment is likely to be a personalised approach. Understanding the genetic background of individual cancer cases and the presence of certain biomarkers can determine the outcome of drug treatment. This is exemplified by colorectal cancer (CRC) where a subset of cases responds to anti-epidermal growth factor receptor (EGFR) antibody therapies including cetuximab, based on the presence or absence of certain mutated alleles. The EU-funded COLTHERES (Modelling and predicting sensitivity to targeted therapies in colorectal cancers) initiative has defined the sensitivity and resistance to agents targeting the EGFR signalling pathway in CRC. The researchers showed that activating K-ras (KRAS) mutations are the cause of resistance to EGFR inhibitors in 30-40 % of patients but other molecular alterations can cause resistance in up to 40 % of other patients as well. The COLTHERES team investigated these mutations and the associated gene expression signatures that can be used to identify more accurately which cancers will respond to EGFR inhibition. Association of KRAS mutations with acquired resistance to targeted therapies for CRC is also observed with B-raf (BRAF) mutations. Inhibition of the BRAF (V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients carrying the same BRAF oncogenic lesion have poor prognosis and show a limited response. Looking into the causative mechanism of this observation, members of the COLTHERES consortium have found that BRAF inhibition causes a rapid feedback activation of EGFR, supporting continued CRC proliferation. This also indicates that BRAF mutant colon cancers might benefit from combination therapy consisting of BRAF and EGFR inhibitors. Importantly, the consortium has been able to detect these mutations in the blood of patients several months before radiographic evidence of disease progression. This offers a time window for treating or reversing drug-resistant malignant clones from emerging. The success of COLTHERES research can be measured by the rapid translation of lab results into clinical trials. Having started experiments in early 2011, the first clinically relevant data was recorded in just under two years.


Colorectal cancer, secondary resistance, EGFR, KRAS, BRAF

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