New Strategies in Colorectal Cancer: Biomarkers of Response to Epidermal Growth Factor Receptor Monoclonal Antibodies and Potential Therapeutic Targets in Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Pathways

Abstract

Initial experience with the epidermal growth factor receptor monoclonal antibodies (EGFR MoAb) in unselected patients with metastatic colorectal cancer (mCRC) showed that most of the treated patients did not derive therapeutic benefit. This outcome has driven the search for biomarkers for this population. Recent advances have further shown the heterogeneous nature of this disease with multiple interlinked pathways being implicated. Two such pathways downstream to the EGFR, mitogen-activated protein kinase (MAPK) and (phosphoinositide 3-kinase) PI3K, have gained increasing attention and become targets for development of novel biomarkers and therapeutic agents. Here, we highlight recent progress.Clin Cancer Res; 16(15); 3811-8. ©2010 AACR.

Biomarkers in Gastrointestinal Cancer: Focus on Colon, Pancreatic and Gastric Cancer

“…Activated Akt phosphorylates downstream protein effectors and amplifies the signaling cascade, enhancing cell proliferation and survival (Ogino et al, 2009b). Based on the current data, it seems that PIK3CA mutation frequency in CRC is probably between 15 and 25% (Dasari & Messersmith, 2010). More than 80% of PIK3CA mutations in CRC occur in exon 9 (60-65%) or exon 20 (20-25%).…”

“…Therefore, ascertainment of PTEN status is usually done on protein level and the recorded frequency of loss of PTEN expression varies from 19% to 36% in CRC. Data on the loss of PTEN are not concordant between primary and metastatic tumors (De Roock et al, 2011) (Dasari & Messersmith, 2010). In addition, PTEN loss in metastatic tumors predicted lack of response to cetuximab and PTEN null metastasis had shorter progression free survival, which was even more significant in KRAS wild-type patients.…”

“…In addition, the V600E mutation could have additional functions, since KRAS and BRAF mutations seems to be mutually exclusive in CRC, with very rare exceptions, suggesting they occur in different tumor types and have different outcomes. Moreover, BRAF mutations are associated with sporadic microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and right sided tumors, whereas mutant KRAS are not (De Roock et al, 2011) (Dasari & Messersmith, 2010).…”

“…Although the relative low concordance rate between the primary and metastatic tumors for PTEN expression could be secondary to selection of clonal populations during metastasis, it could be the subjective nature of immunohistochemistry testing with significant method and observer variability. This consideration and the possible need to analyze PTEN from metastatic tumors may limit the role of PTEN as biomarker in CRC (Dasari & Messersmith, 2010).…”

EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity

“…Because EGF/EGFR signaling is known to promote solid tumor growth through activation of the MAPK/ERK1/2 pathway (Dasari and Messersmith, 2010), we evaluated ERK1/2 involvement in the expression of mPGES-1. Indeed, EGF (25 ng/ml) induced Egr-1 expression and ERK1/2 phosphorylation in the three cell lines analyzed in a time-dependent manner, both events peaking between 15 and 45 min ( Figure 2b).…”