The <i>KRAS</i>-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer

Weidhaas, Joanne B.; Harris, Jonathan; Schaue, Dörthe; Chen, Allen M.; Chin, Robert; Axelrod, Rita; El‐Naggar, Adel K.; Singh, Anurag K.; Galloway, Thomas J.; Raben, David; Wang, Dian; Matthiesen, Chance; Avizonis, Vilija N.; Mañon, R.; Yumen, Omar; Nguyen-Tân, Phuc Félix; Trotti, Andy; Skinner, Heath D.; Zhang, Qiang; Ferris, Robert L.; Sidransky, David; Chung, Christine H.

doi:10.1001/jamaoncol.2016.5478

Cited by 56 publications

(40 citation statements)

References 48 publications

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“…C225 in combination with EGFR not only blocked the secretion of TGF-and signal transduction but also decreased the expression of EGFR on the cell membrane surface (Liao and Carpenter, 2009). Clinically, C225 combined with radiotherapy showed a significant effect on head and neck squamous cell carcinoma and C225 combined with radiotherapy as a routine treatment on head and neck squamous cell carcinoma has been accepted by the majority of doctors (Sok et al, 2006;Pozzi et al, 2016;Suntharalingam et al, 2017 ;Weidhaas et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

EGFR inhibitor C225 Increases the Radio-Sensitivity of Human Breast Cancer Cells

Yao

Peng

et al. 2019

Asian Pac J Cancer Prev

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Objective: This study was undertaken to investigate the effect of C225 on the radio-sensitivity of MDA-MB-231 cells line and to disclosure underlying mechanism. Methods: CCK8 assay was used to measure the proliferation inhibition of C225 on MDA-MB-231 cells. The combined effects of C225 plus radiation on the proliferation of MDA-MB-231 cells were also evaluated by CCK-8 assay. The clonogenic assay was performed to evaluate the cell surviving fractions and to determine the radio-sensitizing effect of C225 on MDA-MB-231 cells. The apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blot analysis was used to detect the expression of p-EGFR, p-Akt, p-P38, and caspase-3. Results: C225 had an inhibiting effect on the proliferation of cells in a concentration-dependent manner. The cloning formation capacity was decreased in C225 plus radiation group. C225 increased radio-sensitivity of cells and led to cell cycle arrest in G0/G1 phase markedly. Cells treated with C225 and radiation predominantly exhibited G0/G1 phase arrest and significant decreased in the fraction of cells in the S phase. Moreover, C225 and radiation significantly increased the apoptosis rate of cells. Decreased cell proliferation was further supported by the down-regulation of p-EGFR and its downstream singling pathway proteins such as p-Akt and p-P38. The up-regulation of the Caspase-3 expression in C225 plus radiation group revealed that C225 could increase radiation-inducing cell apoptosis. Conclusion: C225 could increase the radio-sensitivity of cells, which may be due to the anti-proliferative synergistic effect between C225 and radiation as well as the down-regulation of the PI3K/Akt signaling pathway.

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Section: Discussionmentioning

confidence: 99%

EGFR inhibitor C225 Increases the Radio-Sensitivity of Human Breast Cancer Cells

Yao

Peng

et al. 2019

Asian Pac J Cancer Prev

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“…Others have identified SNPs that may be associated with toxicity and/or outcome in cancer patients treated with EGFR-directed treatment [3,4,6,[17][18][19][20][21]. Lately, studies have suggested that activation of RAS signaling in the tumor is associated with response to cetuximab [28,29]. (C) Figure 2.…”

Section: Discussionmentioning

confidence: 99%

Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial

et al. 2018

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Purpose: To study the associations between development of moderate to severe skin rash, clinical outcome, and single nucleotide polymorphisms (SNPs) in candidate genes in head and neck cancer patients from the DAHANCA 19 trial receiving the EGFR-inhibitor zalutumumab concurrently with radiation treatment. Material and methods: 310 patients were included from the zalutumumab-arm of the DAHANCA 19 study. Nine SNPs in the candidate genes EGFR, EGF, AREG, FCGR2A, FCGR3A, and CCND1 were successfully determined in 294 patients. Clinical endpoints were moderate to severe skin rash within the first 3 weeks of treatment, loco-regional failure (LRF), disease-specific survival (DSS), and overall survival (OS). Results: During the first 3 weeks of treatment, 86% of the patients experienced any grade of rash and 17% experienced a moderate to severe rash. Development of moderate to severe rash was not associated with LRF or DSS but was associated with improved OS, HR 0.40 (95% CI: 0.19-0.82). The effect was similar for patients with p16-negative or p16-positive tumors (p ¼ .90). After adjustment for comorbidity and performance status, the minor alleles of SNPs rs9996584 and rs13104811 located near the AREG gene were significantly associated with increased risk of moderate to severe rash with per-allele odds ratios of 1.61 (1.01-2.54) and 1.56 (1.00-2.44). SNP rs11942466 located close to rs9996584 had a borderline significant association, and none of the other SNPS were significantly associated with risk of skin rash. Conclusions: Moderate to severe skin rash after zalutumumab during radiation treatment was associated with improved OS, independent of HPV/p16-status. Genetic variants in AREG (member of the EGF family) may be associated with increased risk of skin rash.

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“…Notably the KRAS -variant germline and MAPK1 E322K mutation were highlighted in recent literature. Patients harboring a germline mutation in the micro-RNA binding site of KRAS have poorer overall survival [57]. Surprisingly, in a phase III trial in which cetuximab did not confer benefit when added to chemoradiation in unselected HNSCC patients [29], patients with the KRAS -variant (70 of 413 patients tested) had increased OS in the first two years following treatment with cetuximab (HR 0.19; 95% CI, 0.04–0.86; P = 0.03) [57].…”

Section: Insights From Genomic Researchmentioning

confidence: 99%

“…In KRAS -variant patients, TFG-β1 was found to be upregulated; this cytokine has been implicated in suppressing antitumor immunity through regulatory T-cell induction [58]. Authors of this study proposed that through ADCC and improved dendritic cell priming of cytotoxic T lymphocytes, cetuximab bolstered the antitumor immunity otherwise inhibited in KRAS -variant patients [57]. …”

Section: Insights From Genomic Researchmentioning

confidence: 99%

EGFR-targeted therapies in the post-genomic era

Johnson

Grandis

2017

Cancer Metastasis Rev

193

146

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Over ninety percent of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is Food and Drug Administration (FDA) approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.

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The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer

Cited by 56 publications

References 48 publications

EGFR inhibitor C225 Increases the Radio-Sensitivity of Human Breast Cancer Cells

EGFR inhibitor C225 Increases the Radio-Sensitivity of Human Breast Cancer Cells

Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial

EGFR-targeted therapies in the post-genomic era

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