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Multiple roles of PLCĪ³1 in mediating target therapy resistance across different tumor types
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O desenvolvimento e implementaĆ§Ć£o de terapias dirigidas a alvos moleculares especĆficos revolucionou o tratamento do cancro, permitindo uma maior especificidade para cada tipo de tumor e uma reduĆ§Ć£o da toxicidade. A utilizaĆ§Ć£o destas terapias Ć© baseada na expressĆ£o desregulada ou mutaĆ§Ć£o de proteĆnas envolvidas em processos celulares essenciais Ć sobrevivĆŖncia das cĆ©lulas, e das quais os tumores sĆ£o altamente dependentes. No entanto, muitos doentes sĆ£o Ć partida resistentes a estes tratamentos e nĆ£o beneficiam da sua administraĆ§Ć£o, e muitos dos que inicialmente respondem acabam por desenvolver resistĆŖncia e progredir. A identificaĆ§Ć£o de biomarcadores de resposta terapĆŖutica, que permitam selecionar os doentes que beneficiem destes tratamentos Ć© entĆ£o de extrema importĆ¢ncia. Na maioria dos casos existem poucos biomarcadores preditivos e muitos deles apenas identificam uma pequena percentagem de doentes resistentes. Desta forma, mais investigaĆ§Ć£o nesta Ć”rea, assim como de novos alvos terapĆŖuticos que permitam tratar doentes resistentes Ć© fundamental. A PLCĪ³1 Ć© uma proteĆna que possui expressĆ£o ubĆqua e um papel importante na regulaĆ§Ć£o de diversos processos celulares, ao ser um alvo direto de mĆŗltiplas tirosinas cinases, que a fosforilam e ativam. ApĆ³s ativaĆ§Ć£o, a PLCĪ³1 hidrolisa o fosfolĆpido de membrana fosfatidilinositol 4,5-bifosfato (PIP2) em diacilglicerol (DAG) e inositol trifosfato (IP3), e estĆ” envolvida na regulaĆ§Ć£o de mĆŗltiplos processos celulares como proliferaĆ§Ć£o, diferenciaĆ§Ć£o e migraĆ§Ć£o. Diversos estudos demonstraram que a PLCĪ³1 possui um papel importante no desenvolvimento e progressĆ£o tumoral. A sobre expressĆ£o de PLCĪ³1 foi observada em diversos tipos de tumores, incluindo colorretais e mamĆ”rios, e foi associada a um pior prognĆ³stico e a um risco aumentado de desenvolvimento de metĆ”stases. Adicionalmente, mutaƧƵes no gene PLCG1 foram associadas ao desenvolvimento de angiossarcomas e linfomas cutĆ¢neos de cĆ©lulas T. No entanto, apesar da importĆ¢ncia da PLCĪ³1 em mĆŗltiplos processos tumorais e da sua ativaĆ§Ć£o abaixo de proteĆnas que sĆ£o alvos terapĆŖuticos, o seu papel como mediador de resistĆŖncia Ć terapia permanece pouco estudado. Neste contexto, foi identificado que mutaƧƵes no gene PLCG2 (isoforma maioritariamente expressa em cĆ©lulas hematopoiĆ©ticas) estĆ£o associadas Ć resistĆŖncia ao Ibrutinib, um inibidor da tirosina cinase usado no tratamento de leucemia linfocĆtica crĆ³nica. Uma mutaĆ§Ć£o ativadora da PLCG1 foi identificada numa lesĆ£o metastĆ”tica que surgiu apĆ³s tratamento com sunitinib (inibidor de recetores tirosina cinase) num caso de angiossarcoma hepĆ”tico.
Targeted therapies have revolutionized cancer treatment. However, these therapies remain very challenging due to limited efficacy and the existence of innate or acquired mechanisms of resistance. Therefore, there is a great need for new biomarkers that allow a better selection of sensitive patients, and new therapeutic targets to overcome resistance. Phospholipase C gamma 1 (PLCĪ³1) is an important mediator of cell signaling and its expression is dysregulated in multiple tumors, contributing to disease aggressiveness. However, its role in therapy resistance remains unexplored. This work aims to evaluate the role of PLCĪ³1 in the resistance to cetuximab in colorectal cancer (CRC) and endocrine therapy (ET) in breast cancer (BC), exploring its potential as a predictive biomarker and its signaling pathway as a target of therapy. In CRC, we found that levels of PLCĪ³1 in patientsā tumor samples predict responses to cetuximab combined with chemotherapy. Using in vitro and in vivo models, PLCĪ³1 expression was correlated with cetuximab resistance. Mechanistically, PLCĪ³1 signaling bypasses EGFR inhibition by activating ERK and AKT pathways through the binding of PLCĪ³1 SH2 tandem domains to SH2-containing protein tyrosine phosphatase 2 (SHP2). The combination of cetuximab with an SHP2 inhibitor significantly reduced tumor size and the metastatic potential of cetuximab-resistant cancer cells. In BC, PLCĪ³1 expression correlates with sensitivity to tamoxifen and fulvestrant in estrogen receptor (ER) positive BC cell lines. We found that PLCĪ³1 knockout (KO) in the same cell lines decreased viability by reducing ERĪ± signaling and transcriptional activity. Furthermore, PLCĪ³1 binds to ERĪ± and is expressed in the nucleus of cells. Finally, elevated expression of PLCĪ³1 correlates with worse overall survival of luminal A BC patients. Overall, our results show a new role of PLCĪ³1 as a predictive biomarker in different target therapies and tumors. Characterization of PLCĪ³1 signaling downstream of target inhibition can suggest alternative therapeutic approaches to overcome PLCĪ³1-mediated resistance.
Targeted therapies have revolutionized cancer treatment. However, these therapies remain very challenging due to limited efficacy and the existence of innate or acquired mechanisms of resistance. Therefore, there is a great need for new biomarkers that allow a better selection of sensitive patients, and new therapeutic targets to overcome resistance. Phospholipase C gamma 1 (PLCĪ³1) is an important mediator of cell signaling and its expression is dysregulated in multiple tumors, contributing to disease aggressiveness. However, its role in therapy resistance remains unexplored. This work aims to evaluate the role of PLCĪ³1 in the resistance to cetuximab in colorectal cancer (CRC) and endocrine therapy (ET) in breast cancer (BC), exploring its potential as a predictive biomarker and its signaling pathway as a target of therapy. In CRC, we found that levels of PLCĪ³1 in patientsā tumor samples predict responses to cetuximab combined with chemotherapy. Using in vitro and in vivo models, PLCĪ³1 expression was correlated with cetuximab resistance. Mechanistically, PLCĪ³1 signaling bypasses EGFR inhibition by activating ERK and AKT pathways through the binding of PLCĪ³1 SH2 tandem domains to SH2-containing protein tyrosine phosphatase 2 (SHP2). The combination of cetuximab with an SHP2 inhibitor significantly reduced tumor size and the metastatic potential of cetuximab-resistant cancer cells. In BC, PLCĪ³1 expression correlates with sensitivity to tamoxifen and fulvestrant in estrogen receptor (ER) positive BC cell lines. We found that PLCĪ³1 knockout (KO) in the same cell lines decreased viability by reducing ERĪ± signaling and transcriptional activity. Furthermore, PLCĪ³1 binds to ERĪ± and is expressed in the nucleus of cells. Finally, elevated expression of PLCĪ³1 correlates with worse overall survival of luminal A BC patients. Overall, our results show a new role of PLCĪ³1 as a predictive biomarker in different target therapies and tumors. Characterization of PLCĪ³1 signaling downstream of target inhibition can suggest alternative therapeutic approaches to overcome PLCĪ³1-mediated resistance.
DescriĆ§Ć£o
Tese de doutoramento em CiĆŖncias BiomĆ©dicas (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Medicina, 2023.
Palavras-chave
Phospholipase C gamma 1 (PLCĪ³1) Target therapy Therapy resistance Colorectal cancer (CRC) Breast cancer (BC) Fosfolipase C gama 1 (PLCĪ³1) Terapia dirigida ResistĆŖncia Ć terapia Cancro colorretal Cancro da mama