EGFR Inhibitors as Therapeutic Agents in Head and Neck Cancer

Liu, Hanqing; Cracchiolo, Jennifer R.; Beck, Tim N.; Serebriiskii, Ilya G.; Golemis, Erica A.

doi:10.1007/978-1-4614-8815-6_4

Cited by 5 publications

(6 citation statements)

References 244 publications

(282 reference statements)

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“…5E). Analysis of EGFR and HER2 expression is particularly relevant, given the multitude of therapeutic agents that target these receptors (16), their upstream regulation of CDK4/6 cell-cycle activity (40), and the availability of drugs that specifically target CDK4/6 (41). To date, reliable response-predictive biomarkers have not been established for targeted therapies used to treat HNSCC.…”

Section: Discussionmentioning

confidence: 99%

“…This reflects the complementary roles of EGFR, an upstream element of signaling pathways that control cell growth, proliferation and survival, and cell-cycle activity (15–17); expression of additional proteins with functions related to EGFR have also been implicated in the pathogenesis of HPV − HNSCC. These include not only additional EGFR family members, such as HER2 (16), but also components of EGFR/HER2 effector cascades that influence survival: PTEN, PI3K, AKT, and BCAR1 (16–18), and proteins that regulate EGFR/HER2 activity, trafficking, and expression, such as CBL, GRB2, and NSDHL (19, 20). Among these, NSDHL (NADP-dependent steroid dehydrogenase–like enzymes), required for the conversion of squalene to cholesterol (21), has recently been shown to have noncanonical function as a regulator of EGFR recycling (19, 20).…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…Thus far, the only targeted therapeutic approved to treat HNSCC is the monoclonal antibody cetuximab, designed to target the extracellular region of EGFR (Fig. 2; [153]). The clinical impact of cetuximab has been significant in some patients [154], but relatively modest overall [2, 73, 155].…”

Section: Introductionmentioning

confidence: 99%

“…The clinical impact of cetuximab has been significant in some patients [154], but relatively modest overall [2, 73, 155]. Several small molecules, for example lapatinib (targeting EGFR and HER2; [156]), afatinib (targeting EGFR and HER2; [157]) and others (reviewed in [153]), have shown some promise in the treatment of HNSCC. Inter- and intra-disease heterogeneity are likely determining factors that have thus far held back greater success of available therapeutics, and represents one of the key challenges to overcome [19, 24, 151].…”

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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“…Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer globally [ 1 ]. In spite of advances in the development of therapies targeting proteins such as EGFR (epidermal growth factor receptor), other ErbB family members [ 2 , 3 ] or c-MET [ 4 ], which are highly expressed in many SCCHN tumors, the mainstays of treatment for SCCHN remain surgery, cytotoxic chemotherapy, and radiation [ 5 ]. In recent decades, the emergence of SCCHN of the oropharynx related to transforming oncogenic HPV infection has been recognized.…”

Section: Introductionmentioning

confidence: 99%

Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck

et al. 2015

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Locally advanced squamous cell carcinoma of the head and neck (SCCHN) that is not associated with human papillomavirus (HPV) has a poor prognosis in contrast to HPV-positive disease. To better understand the importance of RB1 activity in HPV-negative SCCHN, we investigated the prognostic value of inhibitory CDK4/6 phosphorylation of RB1 on threonine 356 (T356) in archival HPV-negative tumor specimens from patients who underwent surgical resection and adjuvant radiation. We benchmarked pT356RB1 to total RB1, Ki67, pT202/Y204ERK1/2, and TP53, as quantified by automatic quantitative analysis (AQUA), and correlated protein expression with tumor stage and grade. High expression of pT356RB1 but not total RB1 predicted reduced overall survival (OS; P = 0.0295), indicating the potential relevance of post-translational phosphorylation. Paired analysis of The Cancer Genome Atlas (TCGA) data for regulators of this RB1 phosphorylation identified loss or truncating mutation of negative regulator CDKN2A (p16) and elevated expression of the CDK4/6 activator CCND1 (cyclin D) as also predicting poor survival. Given that CDK4/6 inhibitors have been most effective in the context of functional RB1 and low expression or deletion of p16 in other tumor types, these data suggest such agents may merit evaluation in HPV-negative SCCHN, specifically in cases associated with high pT356RB1.

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EGFR Inhibitors as Therapeutic Agents in Head and Neck Cancer

Cited by 5 publications

References 244 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

Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck

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