Presentation Time: 3:35-3:55
Home University: UNC-Chapel Hill
Research Mentor: Channing Der, Pharmacology
Program: CSF
Research Title: YAP1-TAZ-TEAD Inhibition Sensitizes Cells to KRASG12C Inhibition
Mutations in the KRAS oncogene are among the most frequent driver events in human cancers. Following decades of failed efforts, KRAS was considered ‘undruggable’. However, recent efforts in covalently targeting KRAS mutants harboring a G12C mutation has produced the first anti-KRAS therapy to reach FDA approval. That said, acquired mechanisms of drug resistance are certain to limit the long-term effectiveness of G12C inhibition (G12Ci); something that has been reported in the clinic. As such, the search is on for effective strategies by which to sensitize cells to G12Ci. A currently undescribed, mechanism of resistance to G12Ci is the activation of the transcriptional co-activator paralogs, YAP1 and TAZ. Activation of YAP1 has been shown to overcome KRAS addiction in KRAS-mutant cancers. In concordance with these observations, we found that targeting both YAP1 and TAZ significantly sensitizes cells to MRTX1257, analog of the FDA-approved G12Ci MRTX849 (Mirati Therapeutics). As no YAP1/TAZ direct inhibitors exist, a TEAD1-4 dominant-negative construct was utilized to target the TEAD family of transcription factors, the canonical YAP1/TAZ transcriptional partners, as a mean to indirectly inhibit YAP/TAZ activity. We found that inhibition of TEAD1-4 transcriptional activity sensitized cells to G12Ci. We further examined the efficacy of combined TEAD and G12C inhibition using an array of TEAD inhibitors (Vivace Therapeutics) in combination with MRTX1257. This combination produced a highly synergistic reduction in cell viability.