ABS 091: CHI3L1 is a central mediator of crosstalk between EGF/EGFR and Hippo-YAP/TAZ signaling pathways in EGFR lung cancer

Brianna Pham ¹ , Linnaea Mcguinness ¹ , Isabella Fish ¹ , Andres F. Ortiz ¹ , Marlo Hulnick ¹ , Chun G. Lee ¹ ² , Jack A. Elias ¹ ² , Suchitra Kamle ¹ ²

¹ Department of Molecular Microbiology & Immunology at Brown University
² Legoretta Cancer Center, Brown University

Van Wickle (2025) Volume 1, ABS 091

Introduction: Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all cases. Notably, the prevalence of NSCLC with epidermal growth factor receptor (EGFR) mutations is significantly increasing in the U.S. Tyrosine kinase inhibitors (TKIs) are effectively targeted to treat mutated EGFR lung cancer; however, while TKIs initially show favorable responses, patients often acquire secondary EGFR mutations within a year, leading to drug resistance and loss of efficacy. This highlights an urgent need for new therapeutic strategies to overcome TKI resistance in EGFR-mutant NSCLC.

CHI3L1 is a protein expressed by macrophages, neutrophils, epithelial cells, and other immune cells. Elevated circulating levels of CHI3L1 have been observed in various malignancies, including cancers of the prostate, colon, rectum, ovary, kidney, breast, glioblastomas, malignant melanoma, and lung.
The mechanisms driving TKI resistance remain undefined in approximately 50% of cases, and thus effective therapies for these patients have yet to be established. Our studies suggest that CHI3L1 plays a crucial role in EGFR-mutant NSCLC. Specifically, EGFR activation by its physiological ligands (EGF/TGF-α) induces CHI3L1 production, which, in turn, promotes the accumulation of EGF/TGF-α and EGFR. Interestingly, we also observed that CHI3L1 enhances YAP/TAZ expression and facilitates their nuclear translocation in NSCLC. These studies suggest that CHI3L1 is a common regulator of these two signaling pathways which are critically related to the development, progression, and acquisition of TKI resistance in EGFR lung cancer. Given the growth-promoting role of CHI3L1-EGFR and CHI3L1-YAP/TAZ signaling pathways in EGFR-mutant cancers, targeting YAP/TAZ in combination with EGFR inhibition may offer a promising strategy to prevent TKI resistance and cancer recurrence.