Anti-EGFR Therapy: Strategies in Head and Neck Squamous Cell Carcinoma

Oliveira-Silva, Renato José de; Carvalho, Ana Carolina de; Viana, Luciano de Souza; Reis, Rui Manuel

doi:10.2174/1574892811666160309121238

Cited by 14 publications

(13 citation statements)

References 130 publications

(149 reference statements)

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“…EGFR inhibitors are the most promising agents in HNSCC treatment [ 8 ]. Cetuximab, was one of the first drugs developed, and currently the only approved anti-EGFR agent by FDA for HNSCC patients [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Alterations in the epidermal growth factor receptor (EGFR) is one of the major events in head and neck squamous cell carcinoma (HNSCC), being overexpressed in up to 90% of patients [ 5 ]. Despite the high levels of EGFR overexpression, activating EGFR mutations are not frequent and EGFR gene amplification is reported in 24-58% of HNSCC [ 6 – 8 ]. Therefore, EGFR has become an important therapeutic target in HNSCC [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors

et al. 2017

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Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of HNSCC patients. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib, represents a significant therapeutic promise. In this study, we intend to compare the potential cytotoxicity of two anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The higher AKT phosphorylation level was associated with resistance to anti-EGFR agents. Therefore, we further performed drug combinations with anti-AKT agent (MK2206) and AKT1 gene editing, which demonstrated afatinib and allitinib sensitivity restored. Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab. AKT pathway constitutes a predictive marker of allitinib response and combination with AKT inhibitors could restore response and increase treatment success.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors

et al. 2017

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“…In OSCC, there is no exception. Overexpression of EGFR activates many signal pathways, such as RAS/MEK/ERK, PI3K/AKT, and JAK/STAT pathways (Byeon, Ku & Yang, 2019;Nakamura et al, 2019;Oliveira-Silva et al, 2016;Zhang et al, 2018). Secretion of EGFR-contained exosomes from OSCC can be increased by EGF's stimulation.…”

Section: Exosomes Capsuled Protein In Osccmentioning

confidence: 99%

Exosomal cargoes in OSCC: current findings and potential functions

Zhao

Zhang

Liu

et al. 2020

PeerJ

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Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy in head and neck cancer, with high recurrence and mortality. Early diagnosis and efficient therapeutic strategies are vital for the treatment of OSCC patients. Exosomes can be isolated from a broad range of different cell types, implicating them as important factors in the regulation of human physiological and pathological processes. Due to their abundant cargo including proteins, lipids, and nucleic acids, exosomes have played a valuable diagnostic and therapeutic role across multiple diseases, including cancer. In this review, we summarize recent findings concerning the content within and participation of exosomes relating to OSCC and their roles in tumorigenesis, proliferation, migration, invasion, metastasis, and chemoresistance. We conclude this review by looking ahead to their potential utility in providing new methods for treating OSCC to inspire further research in this field.

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“…The second-generation EGFR TKIs such as Dacomitinib and Afatinib are irreversible TKIs. The effects of these EGFR TKIs on HNSCC patient treatment are in evaluation by ongoing clinical trials [9]. …”

Section: Introductionmentioning

confidence: 99%

EGFR tyrosine kinase inhibitors differentially affect autophagy in head and neck squamous cell carcinoma

Cai

Sun

2017

Biochemical and Biophysical Research Communications

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide. The majority of HNSCCs overexpress Epidermal Growth Factor Receptor (EGFR), an essential receptor tyrosine kinase (RTK) that promotes HNSCC growth and metastasis. Therefore, EGFR has been used as an important therapeutic target to treat HNSCC. Inhibition of EGFR stimulates autophagy in cancer cells. However, the role of autophagy in EGFR inhibitor-induced cancer suppression is still in a debate. Here, we reveal that the first- and the second-generation EGFR tyrosine kinase inhibitors (TKIs) differentially affect HNSCC autophagy. The second-generation EGFR TKIs have much stronger effects on autophagy than the first-generation TKIs. The second-generation EGFR TKIs not only promote autophagy initiation signaling but also block autophagic flux by disturbing the lysosomes function, indicating a novel mechanism by which EGFR TKIs modulate cancer cell autophagy. Blocking the initiation of autophagy does not affect the second-generation EGFR TKI-induced HNSCC growth suppression. This suggests that the anti-growth effect of the second-generation EGFR TKIs on HNSCC is not dependent on autophagy.

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Anti-EGFR Therapy: Strategies in Head and Neck Squamous Cell Carcinoma

Cited by 14 publications

References 130 publications

AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors

AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors

Exosomal cargoes in OSCC: current findings and potential functions

EGFR tyrosine kinase inhibitors differentially affect autophagy in head and neck squamous cell carcinoma

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