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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere127552
JournalJCI insight
Volume4
Issue number15
DOIs
Publication statusPublished - Aug 8 2019
Externally publishedYes

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Colorectal Neoplasms
Biomarkers
Therapeutics
Organoids
Drug Therapy
Standard of Care
Combination Drug Therapy
Epidermal Growth Factor
Neoplasms
Alleles
Clinical Trials
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gbenedio, O. M., Bonnans, C., Grun, D., Wang, C. Y., Hatch, A. J., Mahoney, M. R., ... Depeille, P. (2019). RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer. JCI insight, 4(15), [e127552]. https://doi.org/10.1172/jci.insight.127552

RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer. / Gbenedio, Oghenekevwe M.; Bonnans, Caroline; Grun, Delphine; Wang, Chih Yang; Hatch, Ace J.; Mahoney, Michelle R.; Barras, David; Matli, Mary; Miao, Yi; Christopher Garcia, K.; Tejpar, Sabine; Delorenzi, Mauro; Venook, Alan P.; Nixon, Andrew B.; Warren, Robert S.; Roose, Jeroen P.; Depeille, Philippe.

In: JCI insight, Vol. 4, No. 15, e127552, 08.08.2019.

Research output: Contribution to journalArticle

Gbenedio, OM, Bonnans, C, Grun, D, Wang, CY, Hatch, AJ, Mahoney, MR, Barras, D, Matli, M, Miao, Y, Christopher Garcia, K, Tejpar, S, Delorenzi, M, Venook, AP, Nixon, AB, Warren, RS, Roose, JP & Depeille, P 2019, 'RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer', JCI insight, vol. 4, no. 15, e127552. https://doi.org/10.1172/jci.insight.127552
Gbenedio, Oghenekevwe M. ; Bonnans, Caroline ; Grun, Delphine ; Wang, Chih Yang ; Hatch, Ace J. ; Mahoney, Michelle R. ; Barras, David ; Matli, Mary ; Miao, Yi ; Christopher Garcia, K. ; Tejpar, Sabine ; Delorenzi, Mauro ; Venook, Alan P. ; Nixon, Andrew B. ; Warren, Robert S. ; Roose, Jeroen P. ; Depeille, Philippe. / RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer. In: JCI insight. 2019 ; Vol. 4, No. 15.
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AU - Hatch, Ace J.

AU - Mahoney, Michelle R.

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