New Discoveries in Molecular Pathways of Parotid Gland Cancer and their Implications for Therapy

Ruben Alfonso^*
*Correspondence: Ruben Alfonso, Department of Otolaryngology, Isola Tiberina-Gemelli Isola Hospital, 00186 Rome, Italy, Email:

Introduction

Parotid cancer, the most common type of salivary gland malignancy, represents a diverse group of tumours with varying histopathological and molecular characteristics. Despite advancements in surgical techniques and radiotherapy, the prognosis for advanced parotid cancer remains poor. Understanding the molecular underpinnings of parotid cancer is crucial for developing targeted therapies that can improve patient outcomes. This article delves into the molecular pathways implicated in parotid cancer and explores emerging therapeutic targets [1]. The RAS/RAF/MEK/ERK pathway, also known as the MAPK pathway, is integral to cell proliferation and differentiation. Mutations in RAS and RAF genes have been implicated in the pathogenesis of parotid cancer. Inhibitors targeting components of this pathway, such as MEK inhibitors, have shown anti-tumour activity in preclinical studies. Combining MAPK pathway inhibitors with other targeted therapies may enhance therapeutic efficacy.

Description

The Epidermal Growth Factor Receptor (EGFR) pathway is pivotal in cell proliferation, differentiation and survival. Dysregulation of EGFR signalling has been observed in various cancers, including parotid cancer. Overexpression of EGFR and its ligands, along with activating mutations, contribute to tumour growth and resistance to conventional therapies. Targeting EGFR with Tyrosine Kinase Inhibitors (TKIs) and monoclonal antibodies has shown promise in preclinical studies, indicating potential therapeutic applications in parotid cancer. The PI3K/AKT/mTOR pathway plays a central role in cell survival, metabolism and growth. Aberrations in this pathway, such as mutations in PIK3CA and loss of PTEN, are frequently observed in parotid cancer. These alterations lead to constitutive activation of the pathway, promoting oncogenes is and therapy resistance. mTOR inhibitors, such as everolimus, have demonstrated efficacy in preclinical models, suggesting that targeting this pathway could be beneficial in treating parotid cancer [2]. The RAS/RAF/MEK/ERK pathway, also known as the MAPK pathway, is integral to cell proliferation and differentiation. Mutations in RAS and RAF genes have been implicated in the pathogenesis of parotid cancer. Inhibitors targeting components of this pathway, such as MEK inhibitors, have shown anti-tumour activity in preclinical studies. Combining MAPK pathway inhibitors with other targeted therapies may enhance therapeutic efficacy. The NOTCH signalling pathway is involved in cell fate determination and differentiation. Deregulation of NOTCH signalling, including mutations and overexpression, has been identified in parotid cancer. NOTCH inhibitors, such as gamma-secretase inhibitors, are being investigated for their potential to inhibit tumour growth and progression in parotid cancer [3]. The Wnt/β-catenin pathway regulates cell proliferation, migration and stem cell maintenance. Aberrant activation of this pathway, through mutations or overexpression of pathway components, has been observed in parotid cancer. Targeting the Wnt/β-catenin pathway with small molecule inhibitors and monoclonal antibodies holds promise as a therapeutic strategy. Epigenetic alterations, including DNA methylation, histone modifications and non-coding RNAs, play a crucial role in the regulation of gene expression in parotid cancer. These modifications can lead to the silencing of tumour suppressor genes and activation of oncogenes. Epigenetic therapies, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, are being explored for their potential to reverse these changes and inhibit tumour growth [4].

Therapeutic targets and emerging treatments

Given the frequent deregulation of EGFR signalling in parotid cancer, EGFR inhibitors like cetuximab and erlotinib have shown potential in preclinical and early clinical studies. Combining EGFR inhibitors with other targeted therapies may enhance their efficacy and overcome resistance mechanisms [5]. Targeting the PI3K/AKT/mTOR pathway with inhibitors such as everolimus and buparlisib has demonstrated anti-tumour activity in preclinical models of parotid cancer. These inhibitors can potentially be used in combination with other therapies to improve treatment outcomes. MEK inhibitors, such as trametinib, have shown promise in targeting the MAPK pathway in parotid cancer. Their efficacy can be enhanced by combining them with other targeted agents or immunotherapies. NOTCH pathway inhibitors, like gamma-secretase inhibitors, are being investigated for their potential to inhibit tumour growth in parotid cancer. Clinical trials are needed to evaluate their safety and efficacy in patients. Inhibitors targeting the Wnt/β-catenin pathway, such as LGK974, are under investigation for their potential to disrupt aberrant signalling in parotid cancer. These inhibitors may offer a novel therapeutic approach for patients with deregulated Wnt signalling. Epigenetic therapies, including DNA methyltransferase inhibitors (e.g., azacitidine) and histone deacetylase inhibitors (e.g., vorinostat), are being explored for their ability to reverse epigenetic alterations in parotid cancer. These therapies hold promise for reactivating tumour suppressor genes and inhibiting oncogenic pathways.

Parotid cancer, a rare type of salivary gland malignancy, has garnered increasing attention due to advancements in molecular biology that have elucidated its underlying mechanisms. Recent studies have highlighted several key molecular pathways involved in the pathogenesis of parotid cancer, providing new insights and potential therapeutic targets. One significant pathway implicated in parotid cancer is the PI3K/AKT/mTOR pathway. This signalling cascade is crucial for cell growth, proliferation and survival and its deregulation has been observed in various cancers, including parotid malignancies. Mutations and amplifications in genes encoding components of this pathway can lead to uncontrolled cell growth and tumour progression. Targeting the PI3K/AKT/mTOR pathway with specific inhibitors has shown promise in preclinical studies, suggesting a potential therapeutic strategy. Another critical pathway is the MAPK/ERK pathway, which regulates cell differentiation, proliferation and apoptosis. Aberrations in this pathway, such as mutations in RAS and RAF genes, are common in parotid cancer. Inhibitors targeting MEK, a key component of the MAPK/ERK pathway, have demonstrated efficacy in reducing tumour growth in experimental models, indicating their potential as therapeutic agents. The Notch signalling pathway, which plays a vital role in cell fate determination and differentiation, is also implicated in parotid cancer. Alterations in Notch signalling can lead to abnormal cell proliferation and survival. Targeting this pathway with gamma-secretase inhibitors or monoclonal antibodies has shown promise in preclinical studies, offering a potential therapeutic avenue for parotid cancer.

Moreover, the emerging role of epigenetic modifications in parotid cancer pathogenesis cannot be overlooked. DNA methylation, histone modifications and non-coding RNAs have been identified as key regulators of gene expression in parotid cancer. Drugs targeting these epigenetic modifications, such as DNA methyl transferase inhibitors and histone deacetylase inhibitors, are being explored as potential therapeutic options. In addition to these pathways, the role of tumour microenvironment and immune evasion in parotid cancer is gaining attention. Immunotherapeutic approaches, such as immune checkpoint inhibitors, are being investigated to enhance the anti-tumor immune response and improve treatment outcomes.

Conclusion

Advancements in understanding the molecular pathways driving parotid cancer have opened new avenues for targeted therapies. EGFR, PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, NOTCH and Wnt/β-catenin pathways, along with epigenetic modifications, represent critical areas for therapeutic intervention. Continued research and clinical trials are essential to validate these targets and develop effective treatments for parotid cancer. By leveraging molecular insights, we can move closer to personalized and precision medicine approaches, ultimately improving outcomes for patients with this challenging malignancy.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Que, Syril Keena T., Fiona O. Zwald and Chrysalyne D. Schmults. "Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis and staging." J Am Acad Dermatol 78 (2018): 237-247.

   Google Scholar, Crossref, Indexed at

2. Alam, Murad, April Armstrong, Christian Baum and Jeremy S. Bordeaux, et al. "Guidelines of care for the management of cutaneous squamous cell carcinoma." J Am Acad Dermatol 78: 560-578.

   Google Scholar, Crossref, Indexed at

3. Corchado-Cobos, Roberto, Natalia García-Sancha, Rogelio González-Sarmiento and Jesús Pérez-Losada, et al. "Cutaneous squamous cell carcinoma: from biology to therapy." Int J Mol Sci 21 (2020): 2956.

   Google Scholar, Crossref, Indexed at

4. Karia, Pritesh S., Jiali Han and Chrysalyne D. Schmults. "Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis and deaths from disease in the United States, 2012." J Am Acad Dermatol 68 (2013): 957-966.

   Google Scholar, Crossref, Indexed at

5. Thompson, Agnieszka K., Benjamin F. Kelley, Larry J. Prokop and M. Hassan Murad, et al. "Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis and disease-specific death: A systematic review and meta-analysis. JAMA Dermatol 152 (2016): 419-428.

   Google Scholar, Crossref, Indexed at