2021 LCRF-AstraZeneca Research Grant
Antja-Voy Hartley, PhD
Dana-Farber Cancer Institute
Targeting YAP/TEAD bypass activation in Osimertinib-induced drug tolerant cells: a strategy to overcoming tumor recurrence and therapeutic resistance in EGFR-mutant non-small cell lung cancers
Osimertinib is an effective drug for treating mutant epidermal growth factor receptor (EGFR) non-small cell lung cancers. Although many patients respond favorably, one huge barrier to completely curing them remains: not all the tumor cells are eradicated. The remaining cells, dubbed “persisters”, behave quite differently from typical fast-growing tumor cells. First, they adopt a unique state of dormancy (i.e negligible growth) and second, they depend on the YAP/TEAD cancer signaling pathway as a means of escaping death and surviving lethal exposure to osimertinib. Intriguingly, once the drug is removed, these changes are reversible and the “persisters” can quickly regrow to repopulate the tumor and give rise to osimertinib resistance. The fact that these changes are reversible suggests that certain key underlying epigenetic factors (i.e when and how genes are reversibly expressed without changes to the DNA itself) may be at play.
In her research, Dr. Hartley will investigate exactly which type of epigenetic changes are responsible for activating YAP/TEAD signaling in “persisters” following treatment with osimertinib. This knowledge will allow clinicians to identify patients that harbor these “epigenetic marks” and correlate them to the frequency at which we see more activated YAP signaling in tumor cells. Moreover, in the ongoing effort to overcome resistance to osimertinib and improve cure rates, Dr. Hartley proposes to combine osimertinib with a novel YAP/TEAD inhibitor to eliminate “persisters”, decrease the regrowth of tumors once osimertinib is no longer being administered, and ultimately prevent resistance from developing. Finally, she will determine if once resistance develops, are we still able to eliminate these cells with YAP/TEAD inhibition.