Elizaveta Benevolenskaya, PhD

Many patients with non-small cell lung cancer with a mutation in the EGFR gene initially respond well to the treatment. However, almost all of these cancers progress on therapy, even with recently developed EGFR inhibitor drugs such as osimertinib. Delaying acquired tolerance to EGFR inhibitors would clearly improve patient outcomes. The reason for certain cancer cells being left behind (known as persister cells) when the majority of cancer cells die is unknown. Taking into account the variety of cell response to the drug, we recently used a new approach that allowed us to identify metabolic differences between persister cells. We will study these differences in relation to the main pathway regulating cell response to anti-cancer drugs. We will identify persister vulnerabilities and may find new targets for combination drug therapy.

Update:
We showed that many of the processes defining persister cells are regulated by the protein called pRB. In this grant, we used various lung cancer models to address the question whether pRB is critical during the initial steps of developing persistence, and which pRB function should be restored to stop drug resistance. A better understanding of such cell-surviving strategies will be helpful for designing new treatments.

Final Project Update:
Non-small cell lung cancers (NSCLC) with EGFR mutations initially respond well to treatments targeting these mutations. However, most patients eventually see their cancer progress, even with newer drugs like osimertinib. This happens because not all cancer cells are equally affected by the drug; some cells can survive even at drug levels that kill most others. This variation in how cells respond makes it hard to understand the detailed mechanisms behind drug resistance. 

Recent advancements in single-cell analysis have helped us identify the molecular traits that contribute to these drug-tolerant cells. By using single-cell RNA sequencing on patient tumors and cell models, we discovered that many of the processes that allow these persister cells to survive are controlled by a protein called pRB, which is an important tumor suppressor. Our research indicates that drug-tolerant cells develop the ability to grow by changing their metabolism. 

We also investigated other factors in the RB pathway related to this process. Overall, our study has improved our understanding of how the RB pathway contributes to drug resistance. This research is vital for patient care because it highlights weaknesses in persister cells, potentially leading to new targets for combination therapies in lung cancer.