Koyal Ansingkar

Background: Squamous cell carcinoma of the head and neck (HNSCC) refers to cancers affecting the squamous cell epithelial membranes of the nasal, oral, pharyngeal, and laryngeal cavities.¹ HNSCC can be divided into human papilloma virus (HPV)-positive HNSCC and HPV-negative HNSCC (often thought to be due to excessive chewing tobacco consumption). Since the two types are thought to have different pathogenesis models, they might present different therapeutic targets.² PIK3CA has been identified as the most commonly mutated oncogene in SCCHN, both the HPV-negative and HPV-positive forms.^2,3,4

Methods: A literature search on PubMed was conducted using the terms “Squamous Cell Carcinoma of the Head and Neck”, “PIK3CA”, and “genetics”.

Results: Noncanonical PIK3CA mutations (mutations spread throughout the gene) exhibit distinct molecular characteristics compared to canonical mutations (mutations located in specific hot spots), leading to more variability in pathogenesis. 22 of the 32 noncanonical PIK3CA mutations identified were “activating”, indicating their ability to increase cell migration and tumor cell invasion, leading to an increase in PI3Ka signaling.⁴ Bioinformatics analysis of the HPV-positive HNSCC cell genome revealed that changing the ratio of E6 and E7 oncogene expression decreased the function of TP53 and RB, key tumor suppressor genes. PIK3CA mutation expression also induced oropharyngeal carcinoma in genetically engineered mouse models.⁶ PIK3CA overexpression was a stronger driver of HNSCC than PIK3CA mutations.⁸ AKT3, a downstream molecule in the PI3Ka pathway, regulates both the proliferative and immunosuppressive functions of HNSCC, and a combined AKT3 and PIK3CA knockdown resulted in reduced cell proliferation. Moreover, both AKT3 and PIK3CA correlate with stromal cell infiltration, such as infiltration of cancer associated fibroblasts.⁵ Resistance to cetuximab, an epidermal growth factor receptor inhibitor used in conjunction with chemotherapy, was found to be correlated with activating canonical PIK3CA mutations and activation of downstream cascades such as the MAPK and PI3K/AKT pathways.⁷ This indicates a need to therapeutically target downstream effector molecules of the cascade.

Conclusions: Noncanonical PIK3CA mutations may confer resistance to standard PI3K inhibitor therapy. Targeting the PI3K pathway represents a promising therapeutic strategy for HNSCC patients with PIK3CA overexpression, although the potential for resistance to PI3K inhibitor therapy should be understood. Inhibitors targeting PI3K or AKT may counteract the oncogenic effects of PIK3CA overexpression and improve clinical outcomes, although managing drug toxicities would be a challenge. Further research is needed to develop biomarkers of HPV-positive HNSCC and HPV-negative HNSCC and identify specific therapeutic vulnerabilities.

Works Cited:

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