2021 Lung Cancer Research Foundation Pilot Grant
Yang Tian, PhD
Icahn School of Medicine at Mount Sinai
Targeting lung lineage plasticity to suppress Osimertinib-induced drug-tolerant persisters
Genomic discoveries of driver-gene alterations in lung cancer have led to development of effective target therapeutics, however, patients who initially respond to the therapy inevitably experience regrowth of the disease. The reversible drug-tolerant persister (DTP) stage, where cells enter a quiescence to ensure survival, is gaining attention as a major source of non-genetic drug resistance.
Dr Tian’s study seeks to characterize the epigenomic dynamics of DTP stage and to prevent DTP development by targeting the origin of plasticity, thereby avoiding relapse under osimertinib treatment. Their preliminary data showed osimertinib-induced DTP cells exhibited increased heterogeneity, and HOPX, a lineage factor important for lung development and differentiation potential, significantly increased at early DTP stage and is necessary for DTP cell survival.
In this study, they will investigate the dynamic chromatin change during DTP development and determine heterogeneity using single cell sequencing approach. They will also study the role of HOPX and associated developmental pathways in DTP development, to identify novel targets determining the DTP plasticity thereby preventing relapse from heterogeneous pathways to acquire resistance.
Dr. Tian’s findings should not only reveal epigenetic mechanisms by which cancer cells undergo drug resistance transformation but also help develop novel therapeutic strategies, either through chromatin modifying enzymes or specific developmental pathways, to manipulate the activity of critical lineage factors during lung regeneration for patients with minimal residual disease and relapse after osimertinib treatment.
*** This project was awarded the EGFR Resisters Grant.