Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer
| Autor(a) principal: | |
|---|---|
| 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/10451/52256 |
Resumo: | © 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND) |
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Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND)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 (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 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.M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.Repositório da Universidade de LisboaDuarte, RaquelRebelo de Almeida, CátiaNegrão, MagdaFernandes, AfonsoBorralho, PaulaSobral, DanielGallego-Paez, Lina M.Machado, DanielGramaça, JoãoVílchez, JoséXavier, Ana T.Ferreira, Miguel GodinhoMiranda, Ana R.Mansinho, HelderBrito, Maria J.Pacheco, TeresaMarques, CatarinaLucia Costa, AnaMansinho, AndréFior, RitaCosta, LuisMartins, Marta2022-04-07T16:07:17Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/52256engClin Cancer Res. 2022 Mar 15;28(6):1203-12161078-043210.1158/1078-0432.CCR-21-19921557-3265info: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:RCAAP2023-11-08T16:57:22Zoai:repositorio.ul.pt:10451/52256Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:03:23.750094Repositório 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 Duarte, Raquel |
| 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 |
Duarte, Raquel |
| author_facet |
Duarte, Raquel Rebelo de Almeida, Cátia 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, Helder Brito, Maria J. Pacheco, Teresa Marques, Catarina Lucia Costa, Ana Mansinho, André Fior, Rita Costa, Luis Martins, Marta |
| author_role |
author |
| author2 |
Rebelo de Almeida, Cátia 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, Helder Brito, Maria J. Pacheco, Teresa Marques, Catarina Lucia Costa, Ana Mansinho, André Fior, Rita Costa, Luis 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 |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Duarte, Raquel Rebelo de Almeida, Cátia 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, Helder Brito, Maria J. Pacheco, Teresa Marques, Catarina Lucia Costa, Ana Mansinho, André Fior, Rita Costa, Luis Martins, Marta |
| description |
© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND) |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022-04-07T16:07:17Z 2022 2022-01-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/52256 |
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http://hdl.handle.net/10451/52256 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
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Clin Cancer Res. 2022 Mar 15;28(6):1203-1216 1078-0432 10.1158/1078-0432.CCR-21-1992 1557-3265 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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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 |
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