{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T13:19:40Z","timestamp":1776345580550,"version":"3.51.2"},"reference-count":50,"publisher":"American Association for Cancer Research (AACR)","issue":"6","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":1353,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Investigador FCT- Funda\u00e7\u00e3o para a Ci\u00eancia e Technologia","award":["IF\/00409\/2014"],"award-info":[{"award-number":["IF\/00409\/2014"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Technologia","award":["SFRH\/BD\/139138\/2018"],"award-info":[{"award-number":["SFRH\/BD\/139138\/2018"]}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Design:<\/jats:title>\n                    <jats:p>We evaluated the value of EGFR effector phospholipase C gamma 1 (PLC\u03b31) 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 PLC\u03b31-mediated resistance to cetuximab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>In this study, levels of PLC\u03b31 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, PLC\u03b31 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLC\u03b31 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLC\u03b31-resistant cells to cetuximab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Our discoveries reveal the potential of PLC\u03b31 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLC\u03b31-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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/1078-0432.ccr-21-1992","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T16:50:18Z","timestamp":1641228618000},"page":"1203-1216","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Predictive and Therapeutic Implications of a Novel PLC\u03b31\/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer"],"prefix":"10.1158","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2047-2369","authenticated-orcid":false,"given":"Raquel","family":"Cruz-Duarte","sequence":"first","affiliation":[{"name":"1Instituto de Medicina Molecular - Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal."}]},{"given":"C\u00e1tia","family":"Rebelo de Almeida","sequence":"additional","affiliation":[{"name":"2Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal."}]},{"given":"Magda","family":"Negr\u00e3o","sequence":"additional","affiliation":[{"name":"2Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal."}]},{"given":"Afonso","family":"Fernandes","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular - Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal."}]},{"given":"Paula","family":"Borralho","sequence":"additional","affiliation":[{"name":"3Institute of Pathology, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal."}]},{"given":"Daniel","family":"Sobral","sequence":"additional","affiliation":[{"name":"4Universidade Nova Lisboa, UCIBIO, Departamento de Ci\u00eancias da Vida, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal."}]},{"given":"Lina M.","family":"Gallego-Paez","sequence":"additional","affiliation":[{"name":"5BioMed X Institute (GmbH), Im Neuenheimer Feld 583, Heidelberg, Germany."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9727-3907","authenticated-orcid":false,"given":"Daniel","family":"Machado","sequence":"additional","affiliation":[{"name":"6Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal."}]},{"given":"Jo\u00e3o","family":"Grama\u00e7a","sequence":"additional","affiliation":[{"name":"6Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal."}]},{"given":"Jos\u00e9","family":"V\u00edlchez","sequence":"additional","affiliation":[{"name":"6Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal."}]},{"given":"Ana T.","family":"Xavier","sequence":"additional","affiliation":[{"name":"6Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8363-7183","authenticated-orcid":false,"given":"Miguel Godinho","family":"Ferreira","sequence":"additional","affiliation":[{"name":"2Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal."},{"name":"7Institute for Research on Cancer and Aging of Nice (IRCAN), UMR7284 U1081 UNS, Universit\u00e9 C\u00f4te d'Azur, Nice, France."}]},{"given":"Ana R.","family":"Miranda","sequence":"additional","affiliation":[{"name":"8Hemato-Oncologia Division, Hospital Garcia de Orta, Almada, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6872-0675","authenticated-orcid":false,"given":"Helder","family":"Mansinho","sequence":"additional","affiliation":[{"name":"8Hemato-Oncologia Division, Hospital Garcia de Orta, Almada, Portugal."}]},{"given":"Maria J.","family":"Brito","sequence":"additional","affiliation":[{"name":"9Pathology Division, Hospital Garcia de Orta, Almada, Portugal."}]},{"given":"Teresa R.","family":"Pacheco","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular - Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal."},{"name":"10Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3558-3966","authenticated-orcid":false,"given":"Catarina","family":"Abreu","sequence":"additional","affiliation":[{"name":"10Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal."}]},{"given":"Ana","family":"Lucia-Costa","sequence":"additional","affiliation":[{"name":"10Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8771-0838","authenticated-orcid":false,"given":"Andr\u00e9","family":"Mansinho","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular - Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal."},{"name":"10Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal."}]},{"given":"Rita","family":"Fior","sequence":"additional","affiliation":[{"name":"2Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4782-7318","authenticated-orcid":false,"given":"Lu\u00eds","family":"Costa","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular - Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal."},{"name":"10Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0429-9380","authenticated-orcid":false,"given":"Marta","family":"Martins","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular - Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 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