Connor Bossi with Dr. Timothy A. Springer (BCH)
The use of targeted therapy for non-small cell lung cancer (NSCLC) has proven to be effective in inducing initial cell death in cancer cells and has become standard for the treatment of advanced lung cancers with mutations in the epidermal growth factor receptor (EGFR) protein. Eventually, however, cancer cells can develop resistance to the targeted therapies used to treat EGFR-mutant NSCLC. Previous studies have shown that one of the ways in which resistance develops is through the formation of “persister cells” that avoid cell death by entering into a dormant state in which the cells are not growing and dividing, but are able to survive programmed cell death and revert into cancer cells capable of division and growth following drug withdrawal. Little is known about the formation of these persister cells in EGFR-mutant NSCLC, or the conditions that lead to their development. My research will focus on tumor protein 53 (TP53), a tumor suppressor that is estimated to be mutated in approximately half of EGFR-mutant NSCLC patients. Previous studies have shown that TP53 mutations in EGFR-mutant NSCLC may decrease response to targeted therapies and lead to poorer treatment outcomes. The aim of my research project is to determine if TP53 may have a role in persister cell formation, and to examine what this role might be. This will be accomplished by comparing the presence and characteristics of persister cell populations in EGFR-mutant NSCLC with either mutated or wild-type TP53. More specifically, this will be executed by integrating wild-type TP53 into EGFR-mutant NSCLC cell lines with known TP53 mutations. If the cells can integrate functional wild-type TP53 into their genome, they can be treated with targeted therapies to determine if persister cell populations develop in the same way they do in cells with mutated TP53. Monitoring the cells for the presence of persister cell populations and for the characteristics of these persister cells will allow for the investigation of the possible role of TP53 in resistance mechanisms to targeted therapy in EGFR-mutant NSCLC. This may be critical in developing strategies to reduce persister cell populations, elongating the efficacy of targeted therapies, and improving treatment outcomes in patients with EGFR-mutant NSCLC
