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
N1 - Funding Information:
The authors thank the members of the Roose laboratory for active discussion; Marsilius Mues for help with bone marrow reconstitution; Kuang-Yu Jen (University California, Davis) for input in tissue section analysis; and Adam Olsen (UCSF) for suggestions on statistical analyses. Research was supported by the Sandler Program in Basic Science (start-up) and NIH grant 1P01AI091580-01 (to JPR); NIH grants U10CA180821 and U24CA196171 (to the Alliance for Clinical Trials in Oncology); as well as by grants from the Jeannik M. Little-field Foundation (to RSW), the Ministry of Science and Technology, Taiwan (104-2917-I-006-002 to CYW), and the Howard Hughes Medical Institute, Mathers Foundation, Ludwig Institute for Cancer Research, and NIH grant 1R01DK115728 (to KCG). PD is a Mark Foundation Momentum Fellow supported by a fellowship from the Mark Foundation for Cancer Research. Support for the CALGB 80203 analysis comes from an Alliance National Clinical Trials Network (NCTN) grant (U10CA180821, Alliance Chairman’s Grant to Monica Bertagnolli and Suzanne George), as well as an Alliance Biospecimens Grant (U24CA196171, Alliance NCTN Biorepository and Biospecimen Resource Grant to Mark Watson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
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.
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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 -
