Cetuximab in locally advanced head and neck squamous cell carcinoma: Biological mechanisms involved in efficacy, toxicity and resistance

Muraro, Elena; Fanetti, Giuseppe; Lupato, Valentina; Giacomarra, Vittorio; Steffan, Agostino; Gobitti, Carlo; Vaccher, Emanuela; Franchin, Giovanni

doi:10.1016/j.critrevonc.2021.103424

Cited by 20 publications

(18 citation statements)

References 107 publications

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“…Cetuximab, which targets EGFR, is the only approved targeted therapy for the management of locally advanced R/M HNSCC. However, Cetuximab is not used as a monotherapy, but is associated with either radiotherapy [ 1 ] or platinum-based chemotherapy (EXTREME regimen) [ 7 ]. To the best of our knowledge, the molecular mechanisms underlying the cytotoxicity of the EXTREME regimen have not been investigated in detail in HNSCC.…”

Section: Discussionmentioning

confidence: 99%

“…The EXTREME phase III clinical trial evaluated the efficacy of the combination of cetuximab and platinum-based chemotherapy (using cisplatin or carboplatin,) as a first-line treatment in patients with R/M HNSCC. This clinical trial showed that the combination in the EXTREME protocol of cetuximab with platinum-based chemotherapy improves both disease-free and overall survival [ 5 , 6 , 7 ]. Based on this positive outcome, the EXTREME regimen was FDA-approved and became a therapeutic option for the management of patients with R/M HSNCC.…”

Section: Introductionmentioning

confidence: 99%

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The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response

Azevedo

Mourtada

Bour

et al. 2022

Cells

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(1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the patients display a long-lasting objective tumor response. The modulation of cancer cell immunogenicity via a treatment-induced immunogenic cell death is proposed to potentially be able to improve the rate of patients who respond to immune checkpoint blocking immunotherapies. (2) Methods: Using human HNSCC cell line models and a mouse oral cancer syngeneic model, we have analyzed the ability of the EXTREME regimen (combination therapy using the anti-EGFR cetuximab antibody and platinum-based chemotherapy) to modify the immunogenicity of HNSCC cells. (3) Results: We showed that the combination of cetuximab and cisplatin reduces cell growth through both cell cycle inhibition and the induction of apoptotic cell death independently of p53. In addition, different components of the EXTREME regimen were found to induce, to a variable extent, and in a cell-dependent manner, the emission of mediators of immunogenic cell death, including calreticulin, HMGB1, and type I Interferon-responsive chemokines. Interestingly, cetuximab alone or combined with the IC 50 dose of cisplatin can induce an antitumor immune response in vivo, but not when combined with a high dose of cisplatin. (4) Conclusions: Our observations suggest that the EXTREME protocol or cetuximab alone are capable, under conditions of moderate apoptosis induction, of eliciting the mobilization of the immune system and an anti-tumor immune response in HNSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response

Azevedo

Mourtada

Bour

et al. 2022

Cells

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“…Similar to the current trial, diarrhea was dose-limiting and appears to be a class effect of ErbB3 targeting; in contrast, the incidence of acneiform rash on the duligotuzumab arm was lower than for cetuximab alone. Given that the occurrence of acneiform rash remains the only established predictive biomarker for cetuximab efficacy in HNSCC, and may be associated with its immune mechanism of action [28], a fair question is whether the bi-specific antibody construct of duligotuzumab preserved the anti-tumor immune functions of cetuximab [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

Bauman¹,

Saba²

2022

Cancers

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In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8–22.1). Median PFS and OS were 2.2 (95% CI: 1.3–3.6) and 6.6 months (95% CI: 2.7–7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30–44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0–19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.

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“…Here, we demonstrated that CYLD loss induced CTX resistance via inhibition of CME of EGFR and that the N-terminus of CYLD was involved in this phenomenon. Reduced CYLD expression is frequently found, predominantly in invasive lesions in primary HNSCC [ 51 ], which may at least partly explain why CTX is not as effective in this cancer as one would expect from preclinical data [ 11 ]. Our immunohistochemical findings suggest that membrane expression of EGFR may partly reflect the impaired trafficking of this receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Our immunohistochemical findings suggest that membrane expression of EGFR may partly reflect the impaired trafficking of this receptor. Although acquired resistance to CTX often involves persistent activation of the signalling effectors downstream of EGFR [ 51 ], downregulation of CYLD did not block the inhibitory effects of CTX against major downstream effectors, which suggests that EGFR internalization/degradation, rather than the inhibition of downstream signalling, is critical for CTX-induced apoptosis. Indeed, the downregulation of cell-surface EGFR after CTX treatment reportedly predicted antitumour effects in CRC [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

The Tumour Suppressor CYLD Is Required for Clathrin-Mediated Endocytosis of EGFR and Cetuximab-Induced Apoptosis in Head and Neck Squamous Cell Carcinoma

Liu

Shinriki

Maeshiro

et al. 2021

Cancers

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Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and is a target for the therapeutic antibody cetuximab (CTX). However, because only some patients have a significant clinical response to CTX, identification of its predictive biomarkers and potentiation of CTX-based therapies are important. We have recently reported a frequent downregulation of cylindromatosis (CYLD) in primary HNSCC, which led to increased cell invasion and cisplatin resistance. Here, we show that CYLD located mainly in lipid rafts was required for clathrin-mediated endocytosis (CME) and degradation of the EGFR induced by EGF and CTX in HNSCC cells. The N-terminus containing the first cytoskeleton-associated protein-glycine domain of CYLD was responsible for this regulation. Loss of CYLD restricted EGFR to lipid rafts, which suppressed CTX-induced apoptosis without impeding CTX’s inhibitory activity against downstream signalling pathways. Disruption of the lipid rafts with cholesterol-removing agents overcame this resistance by restoring CME and the degradation of EGFR. Regulation of EGFR trafficking by CYLD is thus critical for the antitumour activity of CTX. Our findings suggest the usefulness of a combination of cholesterol-lowering drugs with anti-EGFR antibody therapy in HNSCC.

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Cetuximab in locally advanced head and neck squamous cell carcinoma: Biological mechanisms involved in efficacy, toxicity and resistance

Cited by 20 publications

References 107 publications

The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response

The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

The Tumour Suppressor CYLD Is Required for Clathrin-Mediated Endocytosis of EGFR and Cetuximab-Induced Apoptosis in Head and Neck Squamous Cell Carcinoma

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