YAP1 and RB1 cooperate to regulate lung cancer lineage plasticity and therapeutic resistance

Roswell Park Cancer Institute Corp, Buffalo NY

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Patients with EGFR mutant lung adenocarcinoma (LUAD) are treated with EGFR tyrosine kinase inhibitors (TKI) because they yield better patient outcomes than previous standards of care. EGFR TKI are not curative, however, as virtually all patients progress on therapy due to acquired drug resistance. While genetic mechanisms of acquired EGFR TKI resistance are well understood, non-genetic mechanisms also play an important role. Dynamic and reversible transcriptional adaptations involving lineage state changes support the survival and progression of LUAD cells during treatment. The mechanisms and genetic determinants controlling this LUAD lineage plasticity are not well understood. Advancing fundamental understanding of LUAD lineage plasticity is a prerequisite for the development of therapeutic approaches to predict it, suppress it, and improve therapeutic outcomes. Through analysis of both clinical specimens and experimental models, the collaborating investigators have discovered that minimal residual disease surviving EGFR TKI shows induction of a quiescent, alveolar lineage state. This state is lost in cells proliferating and progressing through EGFR TKI and is replaced by alternative lineage states less dependent on oncogenic EGFR signaling. In currently parallel lines of research within the collaborating investigators labs, YAP1 activity has been demonstrated to drive the alveolar lineage state while RB1 loss accelerates the further transition to alternative, EGFR independent lineage states. These findings suggest YAP1 and RB1 interact to control lineage state transitions during EGFR TKI therapy that ultimately facilitate acquired therapeutic resistance. This ARTNET supplement application is proposed to support collaborative research in two specific aims that will test this hypothesis and validate new genetically engineered mouse models for studying LUAD lineage plasticity in vivo, additionally enabling the study of how non-malignant cells within the tumor microenvironment influence LUAD lineage plasticity and vice versa.