Abstract PS2-11-09: Pan RTK negative regulator LRIG1 as a therapeutic target for endocrine resistance in estrogen receptor-positive breast cancer

Abstract Background: Endocrine resistance affects 30-40% of estrogen receptor-positive (ER+) breast cancer patients within 5 years, often leading to metastatic disease responsible for >90% of breast cancer deaths. Resistance commonly emerges through hyperactivation of receptor tyrosine kinase (RTK) pathways such as HER2, EGFR, FGFR, and IGF-1R. Current clinical approaches targeting individual RTKs have limited durability due to compensatory pathway activation. LRIG1 (Leucine-rich Repeats and Immunoglobulin-like Domains Protein 1) is a pan-negative regulator of RTKs that simultaneously downregulates multiple RTK families through c-CBL-mediated ubiquitination and proteasomal degradation. We hypothesized that LRIG1 restoration could overcome endocrine resistance by targeting multiple RTK pathways simultaneously. Methods: We analyzed LRIG1 gene expression in publicly available data from METABRIC ER+ breast cancer patients who received endocrine therapy (n=1,079). We also evaluated LRIG1 expression and function in T47D and MCF7 ER+ breast cancer cell lines harboring HER2 (S653C, L869R, L755S, V777L) and FGFR2 (K660N, M538I) activating mutations associated with endocrine resistance. LRIG1 modulation was assessed via siRNA knockdown and recombinant LRIG1 protein supplementation. Functional outcomes were measured through proliferation assays (EdU incorporation) and western blot analysis of RTK pathways. Results: Clinical analysis of METABRIC data revealed that ER+ breast cancer patients with higher LRIG1 expression had significantly longer progression-free survival after endocrine therapy (hazard ratio = 0.65, p