Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/151024 |
Resumo: | P. Borralho reports grants from Roche and Novartis, as well as personal fees from Bayer and AstraZeneca outside the submitted work. D. Machado reports personal fees from Amgen and Merck outside the submitted work. H. Mansinho reports grants from AstraZeneca; nonfinancial support from AstraZeneca; and personal fees from Roche, Pfizer, Pierre Fabre, Incyte, BMS, Novartis, Amgen, Servier, Merck Serono, and Grunenthal outside the submitted work. A. Mansinho reports personal fees and nonfinancial support from Merck-Serono during the conduct of the study, as well as personal fees and nonfinancial support from Amgen, Astellas, Bayer, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Vifor Pharma, Pfizer, Pierre Fabre, Roche, and Servier outside the submitted work. L. Costa reports grants from Merck-Serono during the conduct of the study. M. Martins reports grants from Liga Portuguesa Contra o Cancro/Terry Fox and Merck-Serono during the conduct of the study. No disclosures were reported by the other authors. We acknowledge the help of Carla Sousa and Genomed for assessing RAS mutations on tumor samples, the help of Dr. Vasco Rodrigues, and Dr. Rui Marques for their contribution at the Hospital Santa Maria Pharmacy and Champalimaud Fish Platform (C. Certal and J. Monteiro) for excellent animal care. We thank Tom Bunney and Matilda Katan for helpful advice on this project and contribution with PLCg1 plasmids. The authors thank Champalimaud Foundation and M. Godinho Ferreira for the initial support of this project. M. Martins’ research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono. Publisher Copyright: © 2022 The Authors. |
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Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal CancerOncologyCancer ResearchSDG 3 - Good Health and Well-beingP. Borralho reports grants from Roche and Novartis, as well as personal fees from Bayer and AstraZeneca outside the submitted work. D. Machado reports personal fees from Amgen and Merck outside the submitted work. H. Mansinho reports grants from AstraZeneca; nonfinancial support from AstraZeneca; and personal fees from Roche, Pfizer, Pierre Fabre, Incyte, BMS, Novartis, Amgen, Servier, Merck Serono, and Grunenthal outside the submitted work. A. Mansinho reports personal fees and nonfinancial support from Merck-Serono during the conduct of the study, as well as personal fees and nonfinancial support from Amgen, Astellas, Bayer, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Vifor Pharma, Pfizer, Pierre Fabre, Roche, and Servier outside the submitted work. L. Costa reports grants from Merck-Serono during the conduct of the study. M. Martins reports grants from Liga Portuguesa Contra o Cancro/Terry Fox and Merck-Serono during the conduct of the study. No disclosures were reported by the other authors. We acknowledge the help of Carla Sousa and Genomed for assessing RAS mutations on tumor samples, the help of Dr. Vasco Rodrigues, and Dr. Rui Marques for their contribution at the Hospital Santa Maria Pharmacy and Champalimaud Fish Platform (C. Certal and J. Monteiro) for excellent animal care. We thank Tom Bunney and Matilda Katan for helpful advice on this project and contribution with PLCg1 plasmids. The authors thank Champalimaud Foundation and M. Godinho Ferreira for the initial support of this project. M. Martins’ research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono. Publisher Copyright: © 2022 The Authors.Purpose: Cetuximab is an 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, it 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 patients with mCRC (logrank 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 this 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 noncatalytic 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 patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.UCIBIO - Applied Molecular Biosciences UnitDCV - Departamento de Ciências da VidaRUNCruz-Duarte, Raquelde Almeida, Cátia RebeloNegrão, MagdaFernandes, AfonsoBorralho, PaulaSobral, DanielGallego-Paez, Lina M.Machado, DanielGramaça, JoãoVílchez, JoséXavier, Ana T.Ferreira, Miguel GodinhoMiranda, Ana R.Mansinho, HélderBrito, Maria J.Pacheco, Teresa R.Abreu, CatarinaLúcia-Costa, AnaMansinho, AndréFior, RitaCosta, LuísMartins, Marta2023-03-21T22:28:11Z2022-03-152022-03-15T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article14application/pdfhttp://hdl.handle.net/10362/151024engCruz-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., Ferreira, M. G., Miranda, A. R., Mansinho, H., Brito, M. J., Pacheco, T. R., Abreu, C., Lúcia-Costa, A., Mansinho, A., ... Martins, M. (2022). Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer. Clinical Cancer Research, 28(6), 1203-1216. https://doi.org/10.1158/1078-0432.CCR-21-19921078-0432PURE: 56519855https://doi.org/10.1158/1078-0432.CCR-21-1992info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-05-22T18:10:25Zoai:run.unl.pt:10362/151024Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-05-22T18:10:25Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer |
title |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer |
spellingShingle |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer Cruz-Duarte, Raquel Oncology Cancer Research SDG 3 - Good Health and Well-being |
title_short |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer |
title_full |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer |
title_fullStr |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer |
title_full_unstemmed |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer |
title_sort |
Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer |
author |
Cruz-Duarte, Raquel |
author_facet |
Cruz-Duarte, Raquel de Almeida, Cátia Rebelo Negrão, Magda Fernandes, Afonso Borralho, Paula Sobral, Daniel Gallego-Paez, Lina M. Machado, Daniel Gramaça, João Vílchez, José Xavier, Ana T. Ferreira, Miguel Godinho Miranda, Ana R. Mansinho, Hélder Brito, Maria J. Pacheco, Teresa R. Abreu, Catarina Lúcia-Costa, Ana Mansinho, André Fior, Rita Costa, Luís Martins, Marta |
author_role |
author |
author2 |
de Almeida, Cátia Rebelo Negrão, Magda Fernandes, Afonso Borralho, Paula Sobral, Daniel Gallego-Paez, Lina M. Machado, Daniel Gramaça, João Vílchez, José Xavier, Ana T. Ferreira, Miguel Godinho Miranda, Ana R. Mansinho, Hélder Brito, Maria J. Pacheco, Teresa R. Abreu, Catarina Lúcia-Costa, Ana Mansinho, André Fior, Rita Costa, Luís Martins, Marta |
author2_role |
author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
UCIBIO - Applied Molecular Biosciences Unit DCV - Departamento de Ciências da Vida RUN |
dc.contributor.author.fl_str_mv |
Cruz-Duarte, Raquel de Almeida, Cátia Rebelo Negrão, Magda Fernandes, Afonso Borralho, Paula Sobral, Daniel Gallego-Paez, Lina M. Machado, Daniel Gramaça, João Vílchez, José Xavier, Ana T. Ferreira, Miguel Godinho Miranda, Ana R. Mansinho, Hélder Brito, Maria J. Pacheco, Teresa R. Abreu, Catarina Lúcia-Costa, Ana Mansinho, André Fior, Rita Costa, Luís Martins, Marta |
dc.subject.por.fl_str_mv |
Oncology Cancer Research SDG 3 - Good Health and Well-being |
topic |
Oncology Cancer Research SDG 3 - Good Health and Well-being |
description |
P. Borralho reports grants from Roche and Novartis, as well as personal fees from Bayer and AstraZeneca outside the submitted work. D. Machado reports personal fees from Amgen and Merck outside the submitted work. H. Mansinho reports grants from AstraZeneca; nonfinancial support from AstraZeneca; and personal fees from Roche, Pfizer, Pierre Fabre, Incyte, BMS, Novartis, Amgen, Servier, Merck Serono, and Grunenthal outside the submitted work. A. Mansinho reports personal fees and nonfinancial support from Merck-Serono during the conduct of the study, as well as personal fees and nonfinancial support from Amgen, Astellas, Bayer, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Vifor Pharma, Pfizer, Pierre Fabre, Roche, and Servier outside the submitted work. L. Costa reports grants from Merck-Serono during the conduct of the study. M. Martins reports grants from Liga Portuguesa Contra o Cancro/Terry Fox and Merck-Serono during the conduct of the study. No disclosures were reported by the other authors. We acknowledge the help of Carla Sousa and Genomed for assessing RAS mutations on tumor samples, the help of Dr. Vasco Rodrigues, and Dr. Rui Marques for their contribution at the Hospital Santa Maria Pharmacy and Champalimaud Fish Platform (C. Certal and J. Monteiro) for excellent animal care. We thank Tom Bunney and Matilda Katan for helpful advice on this project and contribution with PLCg1 plasmids. The authors thank Champalimaud Foundation and M. Godinho Ferreira for the initial support of this project. M. Martins’ research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono. Publisher Copyright: © 2022 The Authors. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-03-15 2022-03-15T00:00:00Z 2023-03-21T22:28:11Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/151024 |
url |
http://hdl.handle.net/10362/151024 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
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., Ferreira, M. G., Miranda, A. R., Mansinho, H., Brito, M. J., Pacheco, T. R., Abreu, C., Lúcia-Costa, A., Mansinho, A., ... Martins, M. (2022). Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer. Clinical Cancer Research, 28(6), 1203-1216. https://doi.org/10.1158/1078-0432.CCR-21-1992 1078-0432 PURE: 56519855 https://doi.org/10.1158/1078-0432.CCR-21-1992 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
14 application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
mluisa.alvim@gmail.com |
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1817545925447385088 |