PUBLICATION
Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer
- Authors
- Cruz-Duarte, R., de Almeida, C.R., Negrão, M., Fernandes, A., Borralho, P., Sobral, D., Gallego-Paez, L.M., Machado, D., Gramaça, J., Vílchez, J., Xavier, A.T., Godinho Ferreira, M., Miranda, A.R., Mansinho, H., Brito, M.J., Pacheco, T.R., Abreu, C., Lucia-Costa, A., Mansinho, A., Fior, R., Costa, L., Martins, M.
- ID
- ZDB-PUB-220105-3
- Date
- 2022
- Source
- Clinical cancer research : an official journal of the American Association for Cancer Research 28(6): 1203-1216 (Journal)
- Registered Authors
- Fior, Rita
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Cetuximab/pharmacology
- Cetuximab/therapeutic use
- Colonic Neoplasms*/drug therapy
- Colorectal Neoplasms*/drug therapy
- Colorectal Neoplasms*/genetics
- ErbB Receptors/genetics
- Humans
- Mutation
- Phospholipase C gamma/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism*
- Proto-Oncogene Proteins p21(ras)
- Rectal Neoplasms*/drug therapy
- Retrospective Studies
- Zebrafish
- PubMed
- 34980600 Full text @ Clin. Cancer Res.
Citation
Cruz-Duarte, R., de Almeida, C.R., Negrão, M., Fernandes, A., Borralho, P., Sobral, D., Gallego-Paez, L.M., Machado, D., Gramaça, J., Vílchez, J., Xavier, A.T., Godinho Ferreira, M., Miranda, A.R., Mansinho, H., Brito, M.J., Pacheco, T.R., Abreu, C., Lucia-Costa, A., Mansinho, A., Fior, R., Costa, L., Martins, M. (2022) Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 28(6):1203-1216.
Abstract
Purpose Cetuximab is an epidermal growth factor receptor (EGFR)-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance.
Experimental design We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated mCRC patients (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab.
Results In the present study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a non-catalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab.
Conclusions Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in RAS WT mCRC patients. In this way, this work contributes to the development of novel strategies in the medical management and treatment of mCRC patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping