IndraLab

"KRAS mutation, present in 30%-40% of tumors, does not appear to be an independent negative prognostic factor, in that patients in the control arms of studies of EGFR inhibitors in colorectal cancer demonstrate similar outcomes regardless of KRAS mutational status. xref - xref Interestingly, the V600E mutation in BRAF, another gene in the KRAS signal transduction pathway, is also associated with nonresponse to EGFR-targeted therapy based upon early data. xref - xref Subset analyses from the CAIRO-2, CRYSTAL, and PETACC-3 trials suggest that the BRAF V600E mutation, unlike KRAS mutation, is associated with poor prognosis which may confound interpretation of its predictive value. xref - xref BRAF mutations are present in approximately 5% to 10% of colorectal tumors and appear to be mutually exclusive with KRAS mutations. xref , xref , xref , xref BRAF mutation may be more common in patients with the CpG island methylator phenotype (CIMP), which itself has been associated with a positive prognosis, highlighting the complexity of these molecular pathways. xref "

"This observation may have clinical significance for MEDI-565, especially in the treatment of patients with metastatic colorectal cancer where tumors bearing KRAS or BRAF mutations have been associated with reduced response rates to treatment with the EGFR-targeting monoclonal antibodies cetuximab and panitumumab. xref Thus, although EGFR antibody-targeting therapy frequently encounters lower response rates in metastatic colorectal cancer patients harboring these mutations, the patients may respond to MEDI-565 treatment."

"The RAS-RAF-MAPK pathway is a major signaling pathway that triggers cell proliferation upon EGFR ligand binding by activating the KRAS and BRAF genes."

"In addition, activation of downstream signaling pathways of EGFR, such as mutations in KRAS or BRAF, have also been associated with progression of CRC and subsequent resistance to EGFR mAbs."

"Although activating mutations of BRAF (BRAF V600E ) are found only in a small proportion of colon cancers, this poses a great challenge in the quest for a better outcome of the patients, in that BRAF mutations, like mutations in KRAS, are associated with resistance of colon cancer to conventional chemotherapeutic drugs and agents targeting the epidermal growth factor receptor (EGFR) [ xref – xref ]."

"Murine models of NSCLC have been described in which expression of mutated forms of K-ras, Egfr , or BRaf in the lung leads to the development of lung adenocarcinomas or pre-malignant lesions [ xref , xref ]."