Logo do repositório
 
Publicação

Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer

2022-03-15Artigo científico Acesso aberto
Ver registo simples
dc.contributor.authorCruz-Duarte, Raquel
dc.contributor.authorde Almeida, Cátia Rebelo
dc.contributor.authorNegrão, Magda
dc.contributor.authorFernandes, Afonso
dc.contributor.authorBorralho, Paula
dc.contributor.authorSobral, Daniel
dc.contributor.authorGallego-Paez, Lina M.
dc.contributor.authorMachado, Daniel
dc.contributor.authorGramaça, João
dc.contributor.authorVílchez, José
dc.contributor.authorXavier, Ana T.
dc.contributor.authorFerreira, Miguel Godinho
dc.contributor.authorMiranda, Ana R.
dc.contributor.authorMansinho, Hélder
dc.contributor.authorBrito, Maria J.
dc.contributor.authorPacheco, Teresa R.
dc.contributor.authorAbreu, Catarina
dc.contributor.authorLúcia-Costa, Ana
dc.contributor.authorMansinho, André
dc.contributor.authorFior, Rita
dc.contributor.authorCosta, Luís
dc.contributor.authorMartins, Marta
dc.contributor.institutionUCIBIO - Applied Molecular Biosciences Unit
dc.contributor.institutionDCV - Departamento de Ciências da Vida
dc.contributor.pblAACR - American Association for Cancer Research
dc.date.accessioned2023-03-21T22:28:11Z
dc.date.available2023-03-21T22:28:11Z
dc.date.issued2022-03-15
dc.descriptionP. 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.
dc.description.abstractPurpose: 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent14
dc.format.extent1862392
dc.identifier.doi10.1158/1078-0432.CCR-21-1992
dc.identifier.issn1078-0432
dc.identifier.otherPURE: 56519855
dc.identifier.otherPURE UUID: 8bd59773-1afe-417f-a0c3-14061dcb22bf
dc.identifier.otherScopus: 85126388787
dc.identifier.otherPubMed: 34980600
dc.identifier.otherPubMedCentral: PMC9365369
dc.identifier.otherWOS: 000772207100001
dc.identifier.urihttp://hdl.handle.net/10362/151024
dc.identifier.urlhttps://www.scopus.com/pages/publications/85126388787
dc.language.isoeng
dc.peerreviewedyes
dc.relationFunding Information: info:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00409%2F2014%2FCP1236%2FCT0010/PT
dc.relationinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F139138%2F2018/PT
dc.relationPhospholipase C Signalling in Resistance to Anti-RTK Therapy
dc.subjectOncology
dc.subjectCancer Research
dc.subjectSDG 3 - Good Health and Well-being
dc.titlePredictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Canceren
dc.typejournal article
degois.publication.firstPage1203
degois.publication.issue6
degois.publication.lastPage1216
degois.publication.titleClinical Cancer Research
degois.publication.volume28
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/139138/2018
oaire.awardTitlePhospholipase C Signalling in Resistance to Anti-RTK Therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F139138%2F2018/PT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
relation.isProjectOfPublicatione8a97b65-9cf3-4454-b9b2-58d916ade8da
relation.isProjectOfPublication.latestForDiscoverye8a97b65-9cf3-4454-b9b2-58d916ade8da

Ficheiros

Principais
A mostrar 1 - 1 de 1
Miniatura
Nome:
Predictive_and_Therapeutic_Implications_of_a_Novel.pdf
Tamanho:
1.78 MB
Formato:
Adobe Portable Document Format
Ver/Abrir

Coleções

FCT: DCV - Artigos em revista internacional com arbitragem científica