Senescence Escape as a Mechanism of Tarceva Resistance in Retinoblastoma-Negative, EGFR-Positive NSCLC and Therapeutic Strategies to Circumvent
Abstract
Scientific Objective/Rationale: The Food and Drug Administration-approved treatment for EGFR-mutant lung cancer is Tarceva; a small molecule that kills lung cancer cells harboring this genetic defect. Prolonged treatment with Tarceva, however, causes therapeutic resistance, culminating in metastatic disease. This can be caused by molecular changes that make these tumors look and act like small cell lung cancers (SCLC), which are highly metastatic. Molecularly, this is caused by loss of function of genes that regulate cancer cell growth, including the retinoblastoma gene, RB. We propose that Tarceva causes some tumor cells to undergo a type of dormancy, called senescence, instead of cell death. However, senescent cancer cells can escape dormancy and resume proliferation with more aggressive clinical features. We hypothesize that cycles of Tarceva-mediated dormancy and subsequent escape cause the emergence of clinically aggressive tumors with SCLC features. This proposal will investigate whether Tarceva induces senescence in EGFR-mutant lung cancer cells and whether loss of the RB gene occurs during senescence or when cancer cells escape from senescence and resume proliferation. Using molecular techniques, we will deactivate RB during dormancy to determine whether loss of RB permits cancer cells to escape. Finally, we will investigate the ability of certain therapies to cause senescent cell death, thereby eradicating populations of dormant cells that are the source of recurrent disease and metastasis. Area of Emphasis: This proposal is focused on (1) understanding the molecular mechanisms of acquired resistance to treatment and (2) innovative strategy for the treatment of the disease. Impact: This proposal is applicable to all patients diagnosed with EGFR+ lung cancer and will enhance our understanding of how resistance to Tarceva can develop and identify new leads for therapeutic development. Clinically speaking, this research will highlight the need to consider tumor dormancy in treating lung cancer and potentially identify promising leads specifically targeting dormant tumor cells for early clinical trial evaluation (3-4 year timeline). The studies described here are highly translational and will advance understanding and treatment options for EGFR+ lung cancer. Military Relevance: Since risk of lung cancer is substantially elevated in the military, this research is likely to have a direct benefit on this demographic, specifically individuals who smoked for a short time or were exposed to second-hand smoke, environmental toxins, or smoke-containing fuel. These individuals are more likely to develop EGFR-mutant lung adenocarcinoma (the histologic category under study in this proposal). In addition, women are more likely than men to be diagnosed with EGFR-mutant lung adenocarcinoma; thus, the research outlined in this proposal will particularly benefit female military.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010499
Entities
People
- Hayley Mcdaid
Organizations
- Albert Einstein College of Medicine
- United States Army