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Predictive and therapeutic implications of a novel PLCĪ³1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer

2022Journal article Open access
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dc.contributor.authorDuarte, Raquel
dc.contributor.authorRebelo de Almeida, CƔtia
dc.contributor.authorNegrĆ£o, 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.authorGramaƧa, JoĆ£o
dc.contributor.authorVƭlchez, JosƩ
dc.contributor.authorXavier, Ana T.
dc.contributor.authorFerreira, Miguel Godinho
dc.contributor.authorMiranda, Ana R.
dc.contributor.authorMansinho, Helder
dc.contributor.authorBrito, Maria J.
dc.contributor.authorPacheco, Teresa
dc.contributor.authorMarques, Catarina
dc.contributor.authorLucia Costa, Ana
dc.contributor.authorMansinho, AndrƩ
dc.contributor.authorFior, Rita
dc.contributor.authorCosta, Luis
dc.contributor.authorMartins, Marta
dc.date.accessioned2022-04-07T16:07:17Z
dc.date.available2022-04-07T16:07:17Z
dc.date.issued2022
dc.descriptionĀ© 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)pt_PT
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 (PLCĪ³1) 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 PLCĪ³1-mediated resistance to cetuximab. Results: In this study, levels of PLCĪ³1 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, PLCĪ³1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCĪ³1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCĪ³1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCĪ³1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCĪ³1-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.pt_PT
dc.description.sponsorshipM. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- FundaĆ§Ć£o para a CiĆŖncia e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by FundaĆ§Ć£o para a CiĆŖncia 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationClin Cancer Res. 2022 Mar 15;28(6):1203-1216pt_PT
dc.identifier.doi10.1158/1078-0432.CCR-21-1992pt_PT
dc.identifier.eissn1557-3265
dc.identifier.issn1078-0432
dc.identifier.urihttp://hdl.handle.net/10451/52256
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationPhospholipase C epsilon as a Biomarker of Colorectal Cancer Progression
dc.relationPhospholipase C Signalling in Resistance to Anti-RTK Therapy
dc.relation.publisherversionhttps://aacrjournals.org/clincancerrespt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.titlePredictive and therapeutic implications of a novel PLCĪ³1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancerpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitlePhospholipase C epsilon as a Biomarker of Colorectal Cancer Progression
oaire.awardTitlePhospholipase C Signalling in Resistance to Anti-RTK Therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00409%2F2014%2FCP1236%2FCT0010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F139138%2F2018/PT
oaire.citation.endPage1216pt_PT
oaire.citation.issue6pt_PT
oaire.citation.startPage1203pt_PT
oaire.citation.titleClinical Cancer Researchpt_PT
oaire.citation.volume28pt_PT
oaire.fundingStreamInvestigador FCT
person.familyNameDuarte
person.familyNameBorralho Nunes
person.familyNamePacheco
person.familyNameMarques
person.familyNameMansinho
person.familyNameCosta
person.familyNameMartins
person.givenNameRaquel
person.givenNamePaula
person.givenNameTeresa
person.givenNameCatarina
person.givenNameAndrƩ
person.givenNameLuis
person.givenNameMarta
person.identifier.ciencia-idE91A-B8A4-D3B9
person.identifier.ciencia-idB311-6AE6-9A83
person.identifier.ciencia-id7614-C999-F6C7
person.identifier.ciencia-id041E-4ADE-FB64
person.identifier.orcid0000-0002-2047-2369
person.identifier.orcid0000-0002-8556-2090
person.identifier.orcid0000-0002-5506-0233
person.identifier.orcid0000-0003-3558-3966
person.identifier.orcid0000-0001-8771-0838
person.identifier.orcid0000-0002-4782-7318
person.identifier.orcid0000-0003-0429-9380
person.identifier.scopus-author-id55268246400
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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