Abstract
Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) forms a distinct tumor entity with better survival clinical outcome. Numerous underlying molecular mechanisms have been postulated for differences in treatment response, but the impact of MEK/ERK signaling, a main driver of carcinogenesis in various cancers including OPSCC and key player mediating therapy resistance remains elusive. In a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n = 124) were available on tissue microarrays (TMAs) and expression levels of phosphorylated ERK1/2 (pERK1/2) were detected by immunohistochemical staining. Correlations of pERK1/2 expression patterns with clinicopathological features and clinical outcome were evaluated by statistical analysis. A low pERK1/2 expression was strongly associated with HPV-related OPSCC, while primary tumors with high pERK1/2 staining showed a distinctly worse survival outcome and were associated with higher cellular differentiation. Co-activation of both ERK1/2 and AKT was a common event and was associated with unfavorable prognosis in our cohort. However, the combinatorial analysis of pAKT (Ser473) and pERK1/2 did not strengthen the predictive power of pERK1/2, suggesting that pERK1/2 plays a more significant function in OPSCC. In summary, our data provide a compelling experimental and statistical evidence that low levels of tumor cell intrinsic ERK1/2 activation contribute at least in part to the favorable outcome of HPV-related OPSCC. On the other hand, presented findings indicate that non-HPV-related OPSCC with elevated ERK phosphorylation are at high risk for treatment failure and might benefit from targeted therapy of MEK/ERK signaling.
Highlights
Head and neck squamous cell carcinomas (HNSCC) are among the most common solid cancers worldwide with an annual incidence of over 600,000 cases [1]
Patients Is Associated with Human Papillomavirus (HPV) Status and Histopathological Grading
Our findings indicate that a high phosphorylated ERK1/2 (pERK1/2) immunoreactivity score (IRS) was enriched in non-human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as compared findings indicate that a high pERK1/2 IRS was enriched in non-HPV-related OPSCC as compared to to their HPV-related counterparts and linkedwith with good differentiation their HPV-related counterparts andwas was linked good differentiation (Table 1).(Table 1)
Summary
Head and neck squamous cell carcinomas (HNSCC) are among the most common solid cancers worldwide with an annual incidence of over 600,000 cases [1]. Besides the two well-established risk factors, tobacco and alcohol consumption, which account for more than 70% of all HNSCC [2], infection by high-risk types of human papillomavirus (HPV), in particular, HPV16, is a causative factor for an increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) [3,4]. HPV-related OPSCC to be a distinct clinical and molecular entity [5,6]. OPSCC tend to be younger and have better outcomes This has led to the introduction of de-escalation strategies to reduce long-term toxicity [7,8,9]. Current therapeutic paradigms do not adequately address the distinct clinical and biological heterogeneity of HNSCC with varying treatment responses [12,13]. There is an urgent demand in valuable biomarkers and therapeutic targets for HNSCC patients
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