TY - JOUR AU - Gbenedio, Oghenekevwe M. AU - Bonnans, Caroline AU - Grun, Delphine AU - Wang, Chih-Yang AU - Hatch, Ace J. AU - Mahoney, Michelle R. AU - Barras, David AU - Matli, Mary AU - Miao, Yi AU - Garcia, K. Christopher AU - Tejpar, Sabine AU - Delorenzi, Mauro AU - Venook, Alan P. AU - Nixon, Andrew B. AU - Warren, Robert S. AU - Roose, Jeroen P. AU - Depeille, Philippe T1 - RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer PY - 2019/08/08/ AB - Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality, as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncovered that the EGFR pathway component RasGRP1 acts as a CRC tumor suppressor in the context of aberrant Wnt signaling. We found that RasGRP1 suppresses EGF-driven proliferation of colonic epithelial organoids. Having established that RasGRP1 dosage levels impact biology, we next focused on CRC patients. Mining 5 different data platforms, we establish that RasGRP1 expression levels decrease with CRC progression and predict poor clinical outcome of patients. Last, deletion of 1 or 2 Rasgrp1 alleles made CRC spheroids more susceptible to EGFR inhibition. Retrospective analysis of the CALGB 80203 clinical trial showed that addition of anti-EGFR therapy to chemotherapy significantly improved outcome for CRC patients when tumors expressed low levels of RasGRP1 suppressor. In sum, our data support RasGRP1 as a biomarker in the EGFR pathway that has potential relevance to anti-EGFR therapy for CRC patients. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.127552 VL - 4 IS - 15 UR - https://doi.org/10.1172/jci.insight.127552 PB - The American Society for Clinical Investigation ER -