Background:Colorectal cancer is (CRC) one of the commonest cancers and its therapy is still based on few drugs. Currently, no biological criteria are used to choose the most effective of the established drugs for treatment.Methods:A panel of 77 CRC cell lines was tested for sensitivity to 5-fluorouracil (5FU) using the SRB assay. The responses were grouped into three categories and correlated with genetic changes in the cell lines.Results:The strongest and most clearcut correlation was between 5-fluorouracil response and replication error status (mismatch repair deficiency). All the other significant correlations (loss of heterozygosity for DCC and mutations in TGFbIIR) are secondary to the association with replication error status.Interpretation and conclusion:Our findings validate previous analyses based mainly on clinical data, and indicate that replication error status could be a useful guide to 5-fluorouracil-based CRC therapy. Essentially, all previously described correlations with 5FU response are secondary to the association with replication error status.

A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erbb) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated (P = 0.0004) with "triple' wild-type status in KRAS, BRAF, and PIK3CA exon 20. Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 (P = 0.036) and amphiregulin (P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/ PIK3CA mutations (P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcγR polymorphisms.anti-ERBB1 therapy | immune-mediated killing | high throughput screening M onoclonal antibodies against the epidermal growth factor receptor, ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF], including in particular cetuximab, are now commonly used in colorectal cancer (CRC) treatment (1-3). However, only 20% of patients respond to anti-ERBB1 monotherapy (3). The search for predictive markers to improve clinical outcomes (1, 3) has identified that the presence of a KRAS mutation predicts an adverse response leading to routine KRAS testing before anti-ERBB1 therapy (4). However, KRAS mutations are present in only 30-40% of CRC tumors and a significant proportion of KRAS wildtype (WT) patients (50-65%) do not respond to anti-ERBB1 therapy (3). To improve therapeutic outcomes (5), we therefore need to improve understanding of the roles of different antibodykilling mechanisms and the properties of tumors that determine their response to antibody treatment.The relative contributions of immune [for example antibodydependant cellular cytotoxicity (ADCC) and antibody-dependant cellular phagocytosis (ADCP)] and nonimmune processes (competitive blocking of receptor-ligand binding) to tumor response following antibody therapy are not yet clear (5, 6). The FcγR polymorphism has been shown to be an independent predictor of response to cetuximab in CR...