DOI
https://doi.org/10.25772/XA8A-T579
Defense Date
2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Oral Health Research
First Advisor
Anthony Faber
Second Advisor
Iain Morgan
Third Advisor
Hisashi Harada
Fourth Advisor
Sosipatros Boikos
Fifth Advisor
Senthil Radhakrishnan
Abstract
Head and neck squamous cell carcinomas (HNSCC) of the larynx, pharynx and oral cavity is the eighth most common cancer in men in the US and is highly prevalent worldwide. HNSCC has a 5-year survival rate of less than 50%. The identification of targetable genes that are upregulated and activated in HNSCC and biomarkers that can predict patient responses to therapeutic agents targeting these increased gene expressions are needed. In collaboration with Cyril Benes (Massachusetts General Hospital), we conducted a high-throughput screen (HTS) of 948 cancer cell lines and found that a subset of HNSCC is hypersensitive to the Src Homology 2 (SH2) domain-Containing Phosphatase 2 (SHP2) allosteric inhibitor, SHP099. To date, mechanistic studies of SHP2 inhibitors in HNSCC have been lacking. The aim of this research project was therefore to investigate the role of SHP2 inhibition as a particularly effective strategy in the treatment of a subset of HNSCC. We found that the mechanism of action (MOA) whereby SHP099 function relies on the dual suppression of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, through the loss of Grb2-associated binder 1 (GAB1) activation and the disruption of GAB1/p85 complex formation. We further found that this only occurs in the presence of low levels of the epidermal growth factor receptor (EGFR) family ligand epiregulin (EREG) and that adding exogenous EREG rescued such efficacy. We further verified the utility of EREG as a functional marker for SHP2 inhibition responses across HNSCC cell culture models, suggesting that it may represent a viable biomarker to guide the use of SHP2 inhibitors in HNSCC. PI3Kα inhibitors have been shown to exhibit clinical activity in HNSCC bearing PIK3CA mutations or amplifications. Through analyses of models of therapeutic resistance, we found that HNSCC cells that become refractory to PI3Kα inhibition maintain PI3Kα independent activation of the mammalian target of rapamycin (mTOR). In our preliminary data, we further determined that SHP2 and PI3Kα inhibitors are effective in PIK3CA mutant HNSCC when given in combination. This, together with the exquisite sensitivity of HNSCC cells following SHP2 inhibition, suggests that combined SHP2 and PI3Kα inhibition may be efficacious in the treatment of PIK3CA mutant HNSCC tumors. Here, we propose context-specific use of SHP2 inhibitor in HNSCC based on the PI3K pathway genetic status. Importantly, SHP2 and PI3Kα inhibitors are currently in clinical trials for various solid tumors, underscoring the potential for the immediate clinical impact of the work proposed herein. As EGFR is overexpressed in about 90% of HNSCC tumors, molecular therapies targeting this growth factor receptor were thought to hold promise for HNSCC treatment. The modest effect of cetuximab on HNSCC patient survival may be attributable to intrinsic and acquired resistance or by the activity of parallel growth factor pathway signaling in HNSCC. As such, EGFR inhibitors have yet to achieve their full potential in HNSCC. Herein, we explored the potential for the inhibition of the MAPK pathway in combination with EGFR inhibitor treatments in HNSCC cells. In PIK3CA wild-type HNSCC, combination of SHP2 and EGFR inhibitor treatment has demonstrated favorable Preclinical activity relative to that for either single agent, achieving more robust and sustained ERK suppression. Our preliminary results suggest that combining EGFR and SHP2 inhibition can yield efficacious treatment outcomes in HNSCC preclinical models. In light of these results, we propose to develop this project further and to collect the preclinical data necessary for the establishment of a clinical trial combining EGFR and SHP2 inhibition in PIK3CA-wild-type HNSCC. Here, we propose to use SHP2 inhibitors in specific combinations to target molecularly defined subgroups of HNSCC patients.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-6-2022