Therapeutic Efficacy of Combined TBK1 and AKT Inhibition in Breast Cancer
Abstract
Breast cancer is still a life-threatening disease in women: Breast cancer (BC) is the most commonly diagnosed female cancer, and the second leading cause of cancer-related death in the United States with over 232,000 new cases and 40,000 deaths projected in the year 2014. Cancer cells have the ability to divide indefinitely and spread to different parts of the body during metastasis. Metastasis is the most deadly feature of cancer, accounting for greater than 90% of cancer-related mortality. BC is divided into several subtypes depending on the presence of hormone and growth factor receptors on BC cell surface. While hormone and growth factor receptor antagonists have been effective in treating BCs that express these receptors, de novo or acquired resistance to such treatments is common and many cancers will recur and progress. In other words, metastasis and drug resistance are the main causes of cancer-related death; therefore, the identification of new therapeutic targets and strategies is urgently needed. Targeted breast cancer therapy: Targeted cancer therapies are drugs that block the growth and spread of cancer cells by interfering with specific proteins involved in tumor growth and metastasis. These proteins control cell signaling pathways that form a complex communication system to govern basic cellular functions, such as cell division, migration, and survival. By blocking the activities of signaling proteins, targeted cancer therapies can stop cancer cell proliferation and metastasis and may also induce cancer cell death through a process known as apoptosis. PI3K and AKT are the most-studied signaling proteins and control multiple cellular processes to promote tumor growth and metastasis in all BC subtypes. The PI3K-AKT pathway is aberrantly activated in ~80% of BC cases; consequently, many clinical trials are currently being conducted to test therapeutic efficacy of PI3K and AKT inhibitors. However, preliminary results have revealed that BC cells also gain resistance to PI3K and AKT inhibitors. We recently discovered that inhibition of PI3K and AKT leads to increased activation other pro-survival signaling proteins called IKKepsilon and TBK1. IKKepsilon is specifically overexpressed in ~75% of BC cases and is known to promote BC cell survival and metastasis. We also found that combined AKT and TBK1 inhibition synergistically induce apoptosis in all BC cell lines tested. The rationale and objectives: There exist extensive cross-talks among the signaling pathways that control cancer cell proliferation and metastasis. Recent studies revealed that inhibition of one pathway often leads to compensatory increases in other pathways; thus, in order to develop new strategies to effectively treat cancers, it is important to understand the regulatory cross-talks among signaling networks that cooperatively promote cancer cell survival and growth. The rationale of our application is that understanding the cross-talk between the PI3K/AKT and TBK1/IKKepsilon pathways will uncover a novel therapeutic approach for BC. The objectives of the proposed research are to define the mechanisms by which the signaling interplay between the PI3K-AKT and TBK1/IKKepsilon pathways regulates BC cell survival and proliferation and to evaluate the therapeutic efficacy of combined AKT and TBK1 inhibition in a mouse model of BC. Thus, our research project will attempt to address two overarching challenges in BC therapy: (i) identify what drives breast cancer growth and determine how to stop it and (ii) eliminate the mortality associated with metastatic breast cancer. Translational impacts: Every new anti-cancer drug is evaluated in three main clinical phases: Phase I trials collect safety, toxicity, pharmacokinetic, and pharmacodynamic data, Phase II trials identify anti-tumor activity in a specific tumor type and setting, and Phase III trials aim to compare the efficacy of a new treatment with standard of care and can lead
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510351
Entities
People
- Hasem Habelhah
Organizations
- United States Army
- University of Iowa