The Unfolded Protein Response Regulator Grp78 Is A Novel Predictive Biomarker In Colorectal Cancer

Adjuvant fluoropyrimidine-based (5-FU) chemotherapy is a mainstay of treatment for colorectal cancer (CRC), but only provides benefit for a subset of patients. To improve stratification we examined (for the first time in CRC), whether analysis of GRP78 expression provides a predictive biomarker and performed functional studies to examine the role of GRP78 in sensitivity to 5-FU. 396 CRC patient samples were collected in a prospective uniform manner and GRP78 expression was determined by immunohistochemistry on tissue microarrays using a well-validated antibody. Expression was correlated with clinicopathological parameters and survival. The role of GRP78 in 5-FU sensitivity was examined in CRC cells using siRNA, drug inhibition and flow cytometry. GRP78 expression was significantly elevated in cancer tissue (p<0.0001), and correlated with depth of invasion (p=0.029) and stage (p=0.032). Increased overall 5-year survival was associated with high GRP78 expression (p=0.036). Patients with stage II cancers treated by surgery alone, with high GRP78 also had improved survival (71% v 50%; p=0.032). Stage III patients with high GRP78 showed significant benefit from adjuvant chemotherapy (52% vs. 28%; p=0.026), whereas patients with low GRP78 failed to benefit (28% vs. 32%; p=0.805). Low GRP78 was an independent prognostic indicator of reduced overall 5-year survival (p=0.004; HR=1.551; 95%CI 1.155-2.082). In vitro, inhibition of GRP78 reduces apoptosis in response to 5-FU in p53 wild-type cells. GRP78 expression may provide a simple additional risk stratification to inform the adjuvant treatment of CRC and future studies should combine analysis with determination of p53 status.What's new? The Unfolded Protein Response (UPR) is an important cellular adaptation mechanism but can also trigger cell death depending on the nature and severity of the stress stimulus. The authors examined the UPR protein GRP78 as a predictive marker for benefit from adjuvant chemotherapy in patients with advanced colorectal cancer. They find that high expression of GRP78 in cancer tissue is associated with increased overall 5-year survival. In vitro studies demonstrate that GRP78 is a determinant of cellular sensitivity to fluoropyrimidine-based chemotherapy in p53 wild-type cells, providing a molecular basis for the observed patient association. Future studies will demonstrate whether GFP78 measurements may represent a new clinical stratification tool to guide decisions whether patients with colorectal cancer should receive adjuvant chemotherapy.