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

Author:

Cruz-Duarte Raquel1ORCID,Rebelo de Almeida Cátia2,Negrão Magda2,Fernandes Afonso1,Borralho Paula3,Sobral Daniel4,Gallego-Paez Lina M.5,Machado Daniel6ORCID,Gramaça João6,Vílchez José6,Xavier Ana T.6,Ferreira Miguel Godinho27ORCID,Miranda Ana R.8,Mansinho Helder8ORCID,Brito Maria J.9,Pacheco Teresa R.110,Abreu Catarina10ORCID,Lucia-Costa Ana10,Mansinho André110ORCID,Fior Rita2,Costa Luís110ORCID,Martins Marta1ORCID

Affiliation:

1. 1Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

2. 2Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal.

3. 3Institute of Pathology, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

4. 4Universidade Nova Lisboa, UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal.

5. 5BioMed X Institute (GmbH), Im Neuenheimer Feld 583, Heidelberg, Germany.

6. 6Oncology Division, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal.

7. 7Institute for Research on Cancer and Aging of Nice (IRCAN), UMR7284 U1081 UNS, Université Côte d'Azur, Nice, France.

8. 8Hemato-Oncologia Division, Hospital Garcia de Orta, Almada, Portugal.

9. 9Pathology Division, Hospital Garcia de Orta, Almada, Portugal.

10. 10Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.

Abstract

Abstract 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.

Funder

Investigador FCT- Fundação para a Ciência e Technologia

Fundação para a Ciência e Technologia

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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