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 language | English |
|---|---|
| Article number | e127552 |
| Journal | JCI insight |
| Volume | 4 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - Aug 8 2019 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer
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 - Christopher Garcia, K.
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
PY - 2019/8/8
Y1 - 2019/8/8
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85070817411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070817411&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.127552
DO - 10.1172/jci.insight.127552
M3 - Article
C2 - 31237864
AN - SCOPUS:85070817411
VL - 4
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 15
M1 - e127552
ER -