The American Lung Association awarded a $100,000 Lung Cancer Discovery Award to University of Illinois Cancer Center member Elizaveta Benevolenskaya, PhD, for the “Finding cancer vulnerability through analysis of tolerant cell populations” project. Benevolenskaya, part of the Cancer Center’s Cancer Biology research program, explains her work in the edited excerpts below.
Background: In non-small cell lung cancers with an epidermal growth factor receptor (EGFR) mutation, many patients initially respond well to drug treatment but the disease often progresses. Delaying acquired tolerance to EGFR inhibitors would improve patient outcomes. Although not all cancer cells are equally inhibited by drug therapy, there are “persister” cells that are relatively tolerant to the drug concentration that inhibits the majority of the cell population. This limits the clinical success of many types of cancer therapies as it enables certain drug tolerant persisters to resume multiplying.
What We Did: We applied single-cell RNA sequencing to analyses of patient tumors and patient-derived cell models and found that persister cells display characteristic metabolic differences: the acquisition of a proliferative phenotype was associated with changes in glutathione metabolism and antioxidant gene programs. We and other labs previously found that loss of the tumor suppressor pRB is associated with the depletion of nucleotide pools, changes in mitochondrial activity, fatty acid oxidation and glutathione production. The pRB involvement in glutathione synthesis mechanistically lays outside the “classical” pRB functions in cell cycle progression. We found that persisters exhibit the cell cycle and metabolic gene expression signatures that are consistent with inactivation of the RB pathway. Thus, we proposed that drug tolerant persisters acquire the ability to proliferate through the acquisition of a specific metabolic phenotype.
What We’re Doing: Based on our identification of different persister cell populations in cell lines and patient tumors, we now study the dependence of these populations on pRB and metabolic changes in response to pRB inactivation. The American Lung Association project involves development of several relevant biological lung cancer models with the co-principal investigator on the grant, Cancer Center member Debra Tonetti, PhD, part of the Translational Oncology research program. This includes organoids derived from patient tumors with available single cell profiling data. The proposal builds on Dr. Benevolenskaya’s expertise in the RB pathway in collaboration with Cancer Center members Lawrence Feldman, MD, and Ameen Salahudeen, PhD, MD, both of the Translational Oncology research program, and Subhasis Das, PhD, of the Translational Pathology Shared Resource.
What It Means: While this study is addressing basic biological questions on the roles of RB pathway in drug resistance, its use of models of targeted therapies may inform rationally designed schedules of combination therapies against early emerging proliferating persister cells in lung cancer and other cancers.