1. Antibody dependent cellular cytotoxicity-inducing anti-EGFR antibodies as effective therapeutic option for cutaneous melanoma resistant to BRAF inhibitors.
- Author
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Muraro E, Montico B, Lum B, Colizzi F, Giurato G, Salvati A, Guerrieri R, Rizzo A, Comaro E, Canzonieri V, Anichini A, Del Vecchio M, Mortarini R, Milione M, Weisz A, Pizzichetta MA, Simpson F, Dolcetti R, Fratta E, and Sigalotti L
- Subjects
- Animals, Mice, Humans, Proto-Oncogene Proteins B-raf, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Receptor Protein-Tyrosine Kinases metabolism, ErbB Receptors, Antibody-Dependent Cell Cytotoxicity, Melanoma pathology, Skin Neoplasms pathology
- Abstract
Introduction: About 50% of cutaneous melanoma (CM) patients present activating BRAF mutations that can be effectively targeted by BRAF inhibitors (BRAFi). However, 20% of CM patients exhibit intrinsic drug resistance to BRAFi, while most of the others develop adaptive resistance over time. The mechanisms involved in BRAFi resistance are disparate and globally seem to rewire the cellular signaling profile by up-regulating different receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). RTKs inhibitors have not clearly demonstrated anti-tumor activity in BRAFi resistant models. To overcome this issue, we wondered whether the shared up-regulated RTK phenotype associated with BRAFi resistance could be exploited by using immune weapons as the antibody-dependent cell cytotoxicity (ADCC)-mediated effect of anti-RTKs antibodies, and kill tumor cells independently from the mechanistic roots., Methods and Results: By using an in vitro model of BRAFi resistance, we detected increased membrane expression of EGFR, both at mRNA and protein level in 4 out of 9 BRAFi-resistant (VR) CM cultures as compared to their parental sensitive cells. Increased EGFR phosphorylation and AKT activation were observed in the VR CM cultures. EGFR signaling appeared dispensable for maintaining resistance, since small molecule-, antibody- and CRISPR-targeting of EGFR did not restore sensitivity of VR cells to BRAFi. Importantly, immune-targeting of EGFR by the anti-EGFR antibody cetuximab efficiently and specifically killed EGFR-expressing VR CM cells, both in vitro and in humanized mouse models in vivo , triggering ADCC by healthy donors' and patients' peripheral blood cells., Conclusion: Our data demonstrate the efficacy of immune targeting of RTKs expressed by CM relapsing on BRAFi, providing the proof-of-concept supporting the assessment of anti-RTK antibodies in combination therapies in this setting. This strategy might be expected to concomitantly trigger the crosstalk of adaptive immune response leading to a complementing T cell immune rejection of tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Muraro, Montico, Lum, Colizzi, Giurato, Salvati, Guerrieri, Rizzo, Comaro, Canzonieri, Anichini, Del Vecchio, Mortarini, Milione, Weisz, Pizzichetta, Simpson, Dolcetti, Fratta and Sigalotti.)
- Published
- 2024
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