Overcoming Resistance to EGFR Inhibitors in Advanced Head and Neck Cancers
Abstract
This application addresses the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area of head and neck cancer, and the Military Health Focus Area of improving prognosis and identifying improved treatments for individuals suffering from regional and metastatic disease. Head and neck cancers include tumors that arise in the oral cavity (the mouth), the nasal cavity, the pharynx (connecting the nasal cavity and the esophagus), and the larynx (the voicebox). These cancers are typically carcinomas arising from squamous cells and are referred to as head and neck squamous cell carcinomas (HNSCCs). In the United States, approximately 60,000-70,000 people a year are diagnosed with HNSCC. The majority of HNSCCs are caused by mutations and inflammation induced by chronic use of tobacco (either smoking or chewing) and alcohol. Use of alcohol and tobacco by active-duty military personnel and Veterans is common, and HNSCC is a problem in this population. Many HNSCCs are diagnosed at a late stage, after they have spread from their primary site. Treatment options are not very effective for patients diagnosed with these invasive or metastatic HNSCCs, with more than 50% of people diagnosed with invasive cancers, and almost all people diagnosed with metastatic disease, ultimately dying of their cancers. The goal of this proposal is to improve therapy and outcomes for HNSCC. Most of the therapies currently used for patients diagnosed with advanced HNSCC are cytotoxic, based on chemicals that damage DNA. These have challenging side effects. One of the few targeted therapies that works well, in at least some patients with advanced HNSCC, is a group of drugs that block the function of a protein named epidermal growth factor receptor (EGFR), which acts as an oncogene, causing tumor growth and survival. However, not all patients respond to these EGFR inhibitors (EGFRis), and many patients who respond initially, subsequently stop responding. We are studying these two treatment-limiting factors, termed intrinsic resistance and acquired resistance. Based on prior work, a lot of evidence suggests that cancer cells become resistant to EGFRis by increasing the production of another protein Aurora-A (AURKA). AURKA takes over turning on some of the signals normally produced by EGFR and also helps tumors spawn new mutations that can lead to EGFRi resistance. The proposed work seeks to better understand the relation between AURKA and EGFRi, with the specific goal of finding ways to better treat HNSCC patients. We hypothesize that HNSCC cells can increase AURKA in several ways – either by reducing function of the TP53 protein, which turns off AURKA, or by increasing levels of two other proteins, TPX2 and NEDD9, which help AURKA persist in the cells, or by some combination of these methods. We will perform experiments in cell models and in primary HNSCC specimens to determine which of these mechanisms for activating AURKA are present in cells treated with EGFRis. In addition, we will directly test whether the use of AURKA-inhibiting drugs prevents acquired resistance to EGFRis or reverses acquired resistance to these drugs. We will also ask whether combining an inhibitor of WEE1 – a protein that cooperates with AURKA in many important cellular functions – with an inhibitor of AURKA is more effective than just using an inhibitor of AURKA to kill HNSCC cells that are resistant to EGFRis. Based on all of this work, we hope to understand how best to employ EGFRis in HNSCC patients and to develop a strategy to use in patients who do not respond effectively to EGFRis. We hope this work would contribute to improved survival and better quality of life for HNSCC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110487
Entities
People
- Erica Golemis
Organizations
- United States Army