HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Pollock, Netanya; Grandis, Jennifer R.

doi:10.1158/1078-0432.ccr-14-1432

Cited by 86 publications

(85 citation statements)

References 61 publications

(64 reference statements)

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“…In HNSCC, lapatinib, as monotherapy, did not improve OS or progression-free survival (PFS; ref. 47), emphasizing the need for use of response-predictive biomarkers and consideration of combinations with therapeutic agents, such as palbociclib. Afatinib, FDA approved for treatment of non–small cell lung cancer harboring EGFR mutations, has shown some impact on PFS in HNSCC (45, 47).…”

Section: Discussionmentioning

confidence: 99%

“…47), emphasizing the need for use of response-predictive biomarkers and consideration of combinations with therapeutic agents, such as palbociclib. Afatinib, FDA approved for treatment of non–small cell lung cancer harboring EGFR mutations, has shown some impact on PFS in HNSCC (45, 47). Overall, the work in breast cancer by Goel and colleagues (40) and this report support the notion that simultaneous targeting of EGFR and CDKs has enormous clinical potential for some patients.…”

Section: Discussionmentioning

confidence: 99%

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EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer

Beck

Georgopoulos

Shagisultanova

et al. 2016

Molecular Cancer Therapeutics

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Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response–predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6-regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and pT356RB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer

Beck

Georgopoulos

Shagisultanova

et al. 2016

Molecular Cancer Therapeutics

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“…Seiwert et al did not report significant incidence of alteration in HER2 (also known as ERBB2), ERBB3 and ERBB4 and the TCGA also only detected alterations of those genes in a small number of cases (4–6 %; [19]). Nevertheless, alterations in ERBB2 or ERBB3 have been directly linked to resistance to EGFR-targeted therapy and are thus of therapeutic relevance [93]. Mining of TCGA data highlighted that RPPA expression of pHER2 correlated with expression of HER2, and both, pHER2 and HER2 expression correlated with protein expression of EGFR [93], providing some patient data in support of in vivo results in which dual kinase inhibition of EGFR and HER2 enhances response to cetuximab [94].…”

Section: Introductionmentioning

confidence: 99%

Genomic insights into head and neck cancer

Beck

Golemis

2016

Cancers Head Neck

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is frequently impervious to curative treatment efforts. Similar to other cancers associated with prolonged exposure to carcinogens, HNSCCs often have a high burden of mutations, contributing to substantial inter- and intra-tumor heterogeneity. The heterogeneity of this malignancy is further increased by the rising rate of human papillomavirus (HPV)-associated (HPV+) HNSCC, which defines an etiological subtype significantly different from the more common tobacco and alcohol associated HPV-negative (HPV−) HNSCC. Since 2011, application of large scale genome sequencing projects by The Cancer Genome Atlas (TCGA) network and other groups have established extensive datasets to characterize HPV− and HPV+ HNSCC, providing a foundation for advanced molecular diagnoses, identification of potential biomarkers, and therapeutic insights. Some genomic lesions are now appreciated as widely dispersed. For example, HPV− HNSCC characteristically inactivates the cell cycle suppressors TP53 (p53) and CDKN2A (p16), and often amplifies CCND1 (cyclin D), which phosphorylates RB1 to promote cell cycle progression from G1 to S. By contrast, HPV+ HNSCC expresses viral oncogenes E6 and E7, which inhibit TP53 and RB1, and activates the cell cycle regulator E2F1. Frequent activating mutations in PIK3CA and inactivating mutations in NOTCH1 are seen in both subtypes of HNSCC, emphasizing the importance of these pathways. Studies of large patient cohorts have also begun to identify less common genetic alterations, predominantly found in HPV− tumors, which suggest new mechanisms relevant to disease pathogenesis. Targets of these alterations including AJUBA and FAT1, both involved in the regulation of NOTCH/CTNNB1 signaling. Genes involved in oxidative stress, particularly CUL3, KEAP1 and NFE2L2, strongly associated with smoking, have also been identified, and are less well understood mechanistically. Application of sophisticated data-mining approaches, integrating genomic information with profiles of tumor methylation and gene expression, have helped to further yield insights, and in some cases suggest additional approaches to stratify patients for clinical treatment. We here discuss some recent insights built on TCGA and other genomic foundations.

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“…HER2 is a therapeutic target in several tumors such as breast cancer (29)(30)(31)(32), and a predictive factor of response to chemotherapy in various solid malignancies (33)(34)(35)(36). In order to identify improved prognostic indicators for ESCC, the Table I.…”

Section: Discussionmentioning

confidence: 99%

Expression levels of HER2 and MRP1 are not prognostic factors of long-term survival in 829 patients with esophageal squamous cell carcinoma

Yong¹,

Zhu²,

Xu³

et al. 2015

Oncology Letters

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Abstract. Esophageal squamous cell carcinoma (ESCC)is the eighth most frequent neoplasm in China. However, the expression levels of human epidermal growth factor receptor 2 (HER2) and multidrug resistance protein 1 (MRP1) in patients with ESCC remain to be determined. In the present study, 829 ESCC cases were evaluated using immunohistochemistry. The association between the expression levels of HER2 and MRP1 and the patient's clinicopathological factors was analyzed using Fisher's exact test or χ 2 test. Univariate analysis was performed via Kaplan-Meier survival curves, while the Cox proportional hazard model was used for multivariate analysis. A significant correlation was observed between the expression levels of HER2 and the patient's gender (P<0.050), tumor size (P=0.013) and venous/lymphatic invasion (P= 0.039). However, no significant correlation was identified between the expression levels of MRP1 and the clinicopathological factors of the patients. In univariate analysis, gender, differentiation, depth of invasion, clinical stage, adjuvant radiotherapy or chemotherapy and lymph node metastasis were significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients with ESCC (P<0.050). The graphical representation of the Kaplan-Meier estimate curves suggested that the expression levels of HER2 or MRP1 did not exert any influence on prognosis (log-rank test, P>0.050). In multivariate analysis, tumor location, gender, clinical stage, differentiation and lymph node metastasis were identified as independent factors of prognosis in patients with ESCC (P<0.050). However, the expression levels of HER2 or MRP1 were not independently associated with PFS or OS in these patients. In conclusion, the present large-scale study demonstrates that the protein expression levels of HER2 and MRP1 does not exert any influence on the prognosis of ESCC.

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HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Cited by 86 publications

References 61 publications

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer

Genomic insights into head and neck cancer

Expression levels of HER2 and MRP1 are not prognostic factors of long-term survival in 829 patients with esophageal squamous cell carcinoma

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