KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

“…Pharmacological parameters such as the area under the curve (AUC) or the percentage of cell growth inhibition at a clinically relevant drug concentration of 10 mg ml À 1 (ref. 22) closely paralleled the response rates observed in patients 20,21 ( Supplementary Fig. 3a).…”

“…The anti-EGFR monoclonal antibodies cetuximab or panitumumab are approved to treat metastatic CRC but achieve o10% objective response rates in unselected CRC patients when given in monotherapy 20 . Clinical benefit to EGFR blockade is confined to 25% of cases carrying tumours wild-type for KRAS, NRAS and BRAF 21 . To assess whether CRC lines recapitulated the above pharmacogenetic relationships, we determined sensitivity to cetuximab in the entire cell collection over a wide range of drug concentrations (Fig.…”

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Carcinoma of the Colon and Rectum

“…13 PIK3CA mutation has further been associated with poor survival in resectable stage I to III colon cancer, with the adverse effect of PIK3CA mutation potentially limited to patients with KRAS wild-type tumors. 14 PIK3CA mutations have been associated with resistance to anti-EGFR therapy in several studies, 15,16 but not in others. 17 The reasons for the discrepancy are not clear.…”

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

“…28 Unlike in CML, activating mutations of PI3K and KRAS oncogenes are present in a significant proportion of CRC patients and are associated with resistance to EGFR targeted therapy and tumour aggressiveness. 54,62 Constitutive PI3K signalling should inhibit autophagy via mTORC1 (ref 9 ), whereas KRAS mutations are predicted to either inhibit (via PI3K/mTORC1) or activate autophagy. 37 As a result, we first investigated whether EGFR targeted therapy could Cetuximab concentrations and LC3B levels were detected by immunoblotting.…”