Heregulin and HER3 are prognostic biomarkers in oropharyngeal squamous cell carcinoma

Qian, Guoqing; Jiang, Ning; Wang, Dongsheng; Newman, Scott; Kim, Sungjin; Chen, Zhengjia; Garcia, Gabriela; MacBeath, Gavin; Shin, Dong M.; Khuri, Fadlo R.; Chen, Zhuo G.; Saba, Nabil F.

doi:10.1002/cncr.29549

Cited by 43 publications

(34 citation statements)

References 46 publications

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“…Exclusion of the outlying study did not change the results significantly (OR for 5 year OS: 1.30, 95% CI 0.78–2.14, p = 0.31). Similar results were observed in the two studies [24, 32] that reported HR for OS (pooled HR: 3.47, 95% CI 0.78–15.47, p = 0.10, Figure 2B) and when OS was examined at 3 years (pooled OR: 1.25, 95% CI 0.80–1.95, p = 0.33).…”

Section: Resultssupporting

confidence: 89%

“…Once again, there was significant heterogeneity (Cochran Q p < 0.001, I 2 = 82%), although for PFS caused by general heterogeneity and not individual outlying studies. Similar results were observed in the two studies [24, 32] that reported HR for PFS (pooled HR: 1.64, 95% CI 0.94–2.86, p = 0.08, Figure 3B) and when PFS was examined at 3 years (pooled OR: 2.17, 95% CI 0.76–6.21, p = 0.15).…”

Section: Resultssupporting

confidence: 89%

“…Seven were included in the analyses for the specific follow-up time points. Of these, six studies reported data on OS [14, 20, 24, 30, 32, 37] and six studies reported data on intermediate endpoints such as PFS or time to relapse [20, 24, 25, 30, 32, 37]. Figure 1 shows the flow chart for the selection of studies.…”

Section: Resultsmentioning

confidence: 99%

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Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

et al. 2016

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BackgroundNeuregulins (NRG) are a family of epidermal growth factor ligands which act through binding to HER3 and HER4 receptors. NRGs are widely expressed in solid tumors. Their prognostic significance or their role as predictors of benefit from anti-HER3 therapy is not known.ResultsOf 29 included studies, 7 studies reported the association between NRG and outcome. NRG was most commonly expressed in breast, prostate, colon and bladder cancers. NRG expression was not associated with either OS or PFS (HR: 3.47, 95% CI 0.78–15.47, p = 0.10 and HR: 1.64, 95% CI 0.94–2.86, p = 0.08, respectively). In 4 placebo controlled trials of anti-HER3 therapy, the addition of anti-HER3 antibodies to control therapy in unselected patients was not associated with improved PFS (HR: 0.88, 95% CI 0.75–1.04. p = 0.14). However, in patients with high NRG expression, there was significantly delayed progression (HR: 0.35, 95% CI 0.23–0.52, p < 0.001). Anti-HER3 antibodies were associated with increased risk of diarrhea, nausea and rash.MethodsA search of electronically available databases identified studies exploring clinical outcomes based on NRG expression, as well as placebo-controlled trials of HER3-directed therapy reporting results based on NRG expression status. Data were combined in a meta-analysis using generic inverse variance and random effects modeling for studies reporting the hazard ratio (HR) for overall (OS) or progression-free survival (PFS). Mantel-Haenszel random-effect modeling was used for odds ratio (OR) for 3-year and 5-year OS and PFS.ConclusionsNRG expression is not associated with either OS or PFS, but is a predictor of benefit from anti-HER3 antibodies.

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Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 89%

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Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

et al. 2016

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“…Several reports examining large cohorts of HNSCC patients have found HER3 expression to be associated with decreased survival, however, these early studies did not include HPV status in their evaluations (44). More recently, one group reported that HER3 and neuregulin 1 (NRG1), the cognate ligand for HER3, are independently associated with decreased overall survival in oropharyngeal cancer patients (45). In the current study, HER3 was overexpressed in HPV(+) HNSCC cell lines, PDX models, and pharyngeal tumors, where high levels of HER3 protein expression was associated with reduced survival of pharyngeal cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients

Brand

Hartmann

Bhola

et al. 2017

Clinical Cancer Research

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Purpose Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of HNSCCs, where viral expression of the E6 and E7 oncoproteins are necessary for tumor growth and maintenance. Although patients with HPV(+) tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV(+) vs. HPV(−) tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide 3-kinase (PI3K) in HPV(+) tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling, and determined whether HER3 could be a molecular target in HPV(+) HNSCCs. Experimental Design HER3 was investigated as a molecular target in HPV(+) HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV(+) and HPV(−) HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379. Results HER3 was overexpressed in HPV(+) HNSCCs, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV(+) cell lines and PDXs. Conclusions This study uncovers a direct relationship between HPV infection and HER3 in HNSCC, and provides rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV(+) patients.

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“…They also found that patritumab, an antibody specific for HER3, is able to overcome such resistance. Our recent research identified that high heregulin mRNA and high HER3 protein levels are independent prognostic factors for poor overall survival in patients with oropharyngeal squamous cell carcinoma (OPSCC) (38). Our current study further demonstrated both in vitro and in vivo that inhibiting HER3 could resensitize cetuximab-resistant HNSCC cells to this agent.…”

Section: Discussionmentioning

confidence: 99%

HER3 Targeting Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization: Evidence from Cell Line and Patient-Derived Xenograft Models

Wang

Qian

Zhang

et al. 2017

Clinical Cancer Research

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Purpose Our previous work suggested that HER3 inhibition sensitizes HNSCC to EGFR inhibition with cetuximab. This study aimed to define the role of HER3 in cetuximab resistance and the anti-tumor mechanisms of EGFR/HER3 dual targeting in HNSCC. Experimental Design We treated cetuximab-resistant HNSCC UMSCC1-C and parental UMSCC1-P cell lines with anti-EGFR antibody cetuximab, anti-HER3 antibody MM-121, and their combination. We assessed activities of HER2, HER3 and downstream signaling pathways by Western blotting, and cell growth by sulforhodamine B (SRB) and colony formation assays. HER3-specific shRNA was used to confirm the role of HER3 in cetuximab response. The combined efficacy and alterations in biomarkers were evaluated in UMSCC1-C xenograft and patient-derived xenograft (PDX) models. Results Cetuximab treatment induced HER3 activation and HER2/HER3 dimerization in HNSCC cell lines. Combined treatment with cetuximab and MM-121 blocked EGFR and HER3 activities and inhibited PI3K/AKT and ERK signaling pathways and HNSCC cell growth more effectively than each antibody alone. HER3 knockdown reduced HER2 activation and re-sensitized cells to cetuximab. Cetuximab-resistant xenografts and PDX models revealed greater efficacy of dual EGFR and HER3 inhibition compared to single antibodies. In PDX tissue samples, cetuximab induced HER3 expression and MM-121 reduced AKT activity. Conclusion Clinically relevant PDX models demonstrate that dual targeting of EGFR and HER3 is superior to EGFR targeting alone in HNSCC. Our study illustrates the upregulation of HER3 by cetuximab as one mechanism underlying resistance to EGFR inhibition in HNSCC, supporting further clinical investigations using multiple targeting strategies in patients who have failed cetuximab-based therapy.

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Heregulin and HER3 are prognostic biomarkers in oropharyngeal squamous cell carcinoma

Cited by 43 publications

References 46 publications

Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies

Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients

HER3 Targeting Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization: Evidence from Cell Line and Patient-Derived Xenograft Models

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