The Role of Targeted Therapy and Oncogene Dependence on the PIK3CA Mutation

Abstract

Objectives:

(1) Determine the role of oncogene dependence on one of the more common and targetable oncogenes in head and neck squamous cell carcinoma (HNSCC) PIK3CA. (2) Evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies.

Methods:

A basic science study was performed to test the hypothesis that PI3KCA hot spot mutations confer increased sensitivity or oncogene addiction to PI3K and related inhibitors. The PI3KCA hotspot mutations—E545K and H1047R—were engineered within the HNSCC cell line SCC25. Cell viability was measured using high throughput microscopy to determine the survivability cell lines expressing the hotspot mutations compared with control cell lines when treated with increasing concentrations of newly developed targeted therapies 17-AAG, GDC-0941, and Trametinib.

Results:

Surprisingly, hotspot E545K and H1047R mutations conferred increased rather than reduced survivability when treated with increased concentrations of the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and Trametinib compared to the SCC25 control cell lines.

Conclusions:

(1) The PIK3CA mutations within our engineered cell model did not lead to oncogene dependent cell death when treated with targeted therapy including direct inhibition of the Phosphatidylinositol 3-kinase (PI3K) enzyme. (2) Oncogene addiction to PIK3CA hot spot mutations, if it occurs, is likely to evolve in vivo in the context of additional molecular changes that remain to be identified.