RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer
Oghenekevwe M. Gbenedio, … , Jeroen P. Roose, Philippe Depeille
Oghenekevwe M. Gbenedio, … , Jeroen P. Roose, Philippe Depeille
Published August 8, 2019; First published June 25, 2019
Citation Information: JCI Insight. 2019;4(15):e127552. https://doi.org/10.1172/jci.insight.127552.
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Research Article Gastroenterology Therapeutics

RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer

Abstract

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.

Authors

Oghenekevwe M. Gbenedio, Caroline Bonnans, Delphine Grun, Chih-Yang Wang, Ace J. Hatch, Michelle R. Mahoney, David Barras, Mary Matli, Yi Miao, K. Christopher Garcia, Sabine Tejpar, Mauro Delorenzi, Alan P. Venook, Andrew B. Nixon, Robert S. Warren, Jeroen P. Roose, Philippe Depeille

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Figure 3

RasGRP1 is a prognostic marker for CRC.

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RasGRP1 is a prognostic marker for CRC. (A–C) RasGRP1 expression in huma...
(A–C) RasGRP1 expression in human CRC patients from the TCGA Colorectal Adenocarcinoma data sets. Expression of RasGRP1 in patients with WT versus mutant APC (A), WT versus mutant TP53 (B), and WT versus mutant KRAS (C). Statistical analyses were performed using unpaired t test; *P < 0.05. (D) Analysis of relative RasGRP1 expression using TCGA data as in A–C, organized by number of mutations in APC, TP53, and KRAS. *P < 0.05 (Dunnett’s test). (E) Analysis of relative SOS1 expression using TCGA data as in B–D, organized by number of mutations in APC, TP53, and KRAS. (F) RasGRP1 mRNA expression determined by TaqMan PCR on liver metastasis samples surgically removed from 124 patients with metastatic CRC. KRASmut, n = 87; KRASWT, n = 37. (G) Imunohistochemistry for RasGRP1 (brown staining) on liver metastasis patient samples selected from G with either low or high RasGRP1 levels. Scale bars: 20 μm. (H) Kaplan-Meier overall survival curve for stage II and III PETACC-3 CRC patients (n = 282) carrying KRAS mutation, divided in 2 equal groups of 141 patients expressing high or low levels of RasGRP1 (*P = 0.02, log-rank [Mantel-Cox] test). (I) Analysis of RasGRP1 and SOS1 expression in matched primary and metastatic tumors from patients with metastatic CRC in the MOSAIC program. Gene expression levels (in log2 of RPKM) for RasGRP1 and SOS1 in metastases (red dots) were compared with levels in primary tumors (blue dots). Red lines and blue lines represent increase and decrease in expression level, respectively. Student’s t test was performed to assess the statistical significance between comparisons. *P < 0.05.