Abstract 2244: Pro-metastatic kinase network inhibition to treat drug-resistant triple-negative breast cancer.

Abstract Metastatic triple-negative breast cancer (mTNBC) has high mortality rates and limited therapeutic options. Chemotherapy, the basis of standard approved therapy for mTNBC, targets rapidly dividing cells but fails to eliminate the stem-like cells that drive metastasis. While kinases are promising drug targets, single-kinase inhibitors have been largely ineffective in mTNBC due to tumor heterogeneity, drug resistance, and the absence of predictive biomarkers. Our strategy is to identify and target kinase networks in pro-metastatic tumor cells that are upregulated in drug-resistant cells or specifically targeted by physiological regulators of metastasis. We initially utilized this approach to overcome AKT resistance in mTNBC. Employing a kinase activity assay (MIB-MS profiling), we demonstrated upregulation of Src family and ATM/ATR kinase networks following treatment of patient-derived, drug-resistant mTNBC organoids with the AKT inhibitor capivasertib. Sequential administration of capivasertib and dasatinib to target the Src family did not reduce organoid viability but did disrupt organoid formation and self-renewal, suggesting effective inhibition of metastatic potential. Building on our previous work, we then optimized a multi-kinase inhibitor regimen that mimics a physiological metastasis suppressor by targeting key stress-responsive kinase networks (ERK1/2, p38, JNK, and MLK). This low-dose drug combination (4MAPKi) prevented both TNBC metastasis and activation of compensatory pathways. We further refined this to a three-drug regimen (Ralimetinib, JNK-in-8, and Trametinib) that inhibits stress kinase networks, pro-motility gene expression and TNBC cell invasion in organoid assays. Importantly, combining this antimetastatic regimen with standard chemotherapy sensitized both TNBC cells and organoids to treatment. Ongoing studies focus on optimizing treatment efficacy with antibody-drug conjugates, characterizing kinase network targets specific for other metastasis regulators such as transcription factors, and exploring kinase networks as biomarkers for treatment resistance. Our long-term goal is to develop a low-toxicity, multi-kinase inhibitor strategy that reprograms metastatic TNBC cells, enhancing the efficacy and durability of their response to chemotherapy and improving clinical outcomes. Citation Format: Margarite Matossian, Madeline Henn Bungert, Kent Schechter, Long Chi Nguyen, Michael East, Denis O. Okumu, Rita Nanda, Gary L. Johnson, Marsha R. Rosner. Pro-metastatic kinase network inhibition to treat drug-resistant triple-negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2244.