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, p0.0001). Patients whose cancer recurred had significantly lower LRIG1 expression compared to those without recurrence (p0.0001). In endocrine-resistant cell lines with activating RTK mutations, LRIG1 was consistently downregulated compared to controls. HER2-activating mutants showed decreased LRIG1 protein expression and increased phosphorylated HER2. Treatment with RTK inhibitors (Neratinib for HER2 and FIIN3 for FGFR) significantly restored LRIG1 expression in resistant cells. Recombinant LRIG1 supplementation (0-20 μg/mL) in LRIG1-knockdown T47D cells significantly decreased proliferation in a dose-dependent manner, with greater than 50% reduction at the highest concentration tested. Conclusions: LRIG1 represents a clinically actionable biomarker and potential therapeutic target in endocrine-resistant ER+ breast cancer. The inverse relationship between LRIG1 expression and RTK pathway activation, coupled with the restoration of LRIG1 by RTK inhibitors, suggests a therapeutically exploitable bidirectional relationship. Exogenous LRIG1 supplementation effectively suppresses proliferation in endocrine-resistant models, supporting its development as a first-in-class pan-RTK therapeutic adjuvant. This approach could address the fundamental limitation of current targeted therapies by simultaneously blocking multiple resistance pathways, potentially offering new treatment options for patients with limited therapeutic alternatives. Citation Format: B. D. Jenkins, K. S. Ingram, A. Hokulani Pajimola, J. Morgan, E. Liu, U. Nayar. Pan RTK negative regulator LRIG1 as a therapeutic target for endocrine resistance in estrogen receptor-positive breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-09.
Jenkins et al. (Tue,) studied this question.
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