Abstract 1721: Dual targeting of JAK2 and TrkA inhibits breast cancer cell stemness, enhances apoptosis, and delays tumor growth of triple-negative and HER2-enriched breast cancers

Abstract Despite the current standard of care, metastatic triple-negative breast cancer (TNBC) and HER2-enriched breast cancer remain difficult to treat due to limited actionable targets, poor response to treatment, and intrinsic/acquired therapeutic resistance. Thus, more effective therapies are needed to reduce the high mortality rates associated with metastatic TNBC and HER2-enriched breast cancer. The Janus Kinase 2 (JAK2)-Signal Transducer and Activator of Transcription 3 (STAT3) pathway is dysregulated in multiple solid tumors, including breast cancer, and is being investigated as a therapeutic target. Similarly, Tropomyosin receptor tyrosine kinase A (TrkA) is an emerging target in metastatic breast cancers. The prevalence of aberrant JAK2 or TrkA signaling led to the development and FDA approval of orally active, selective inhibitors for JAK2 (pacritinib) and TrkA (entrectinib, larotrectinib). However, breast cancer patients receiving either JAK2 or TrkA inhibitors showed suboptimal clinical response, suggesting that oncogenic signaling events are sustained in the absence of either JAK2 or TrkA activity. In support of this paradigm, we previously reported a novel signaling crosstalk between the JAK2-STAT3 and TrkA pathways (Cancers, 10:2340-2360, 2021). We found that JAK2 and TrkA are preferentially co-activated in TNBC and HER2-enriched breast cancer, and both kinases converge to phosphorylate STAT3 to drive gene transcription and enhance breast cancer cell stemness. The observed significant functional crosstalk between JAK2 and TrkA pathways suggest that co-inhibition of these pathways would greatly benefit breast cancer patients with co-activation of these pathways. In this study, we aimed to determine the therapeutic utility of dual targeting JAK2 and TrkA in TNBC and HER2-enriched breast cancer using FDA-approved selective inhibitors. Our data showed that JAK2 and TrkA inhibitors synergize to reduce breast cancer cell viability in vitro. Our study further revealed that co-inhibition of JAK2 and TrkA potently inhibits breast cancer cell stemness since co-inhibition of these kinases significantly reduces the CD44high/CD24low cell population, mammosphere formation, and ALDH activity to a greater extent than vehicle or monotherapies. We also found that co-inhibition of JAK2 and TrkA more effectively induces apoptosis of breast cancer cells, as indicated by Annexin V flow cytometry, Western blot analysis for cleaved PARP, and Caspase 3/7 activity. Importantly, our in vivo studies showed that co-inhibition of JAK2 and TrkA significantly delays mammary tumor growth using cell line-derived and patient-derived xenograft breast cancer mouse models. Taken together, our data illustrates the therapeutic utility of dual targeting JAK2 and TrkA in metastatic TNBC and HER2-enriched breast cancers. Citation Format: Angelina T. Regua, Mariana K. Najjar, Grace L. Wong, Sara G. Manore, Austin Arrigo, Hui-Wen Lo. Dual targeting of JAK2 and TrkA inhibits breast cancer cell stemness, enhances apoptosis, and delays tumor growth of triple-negative and HER2-enriched breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1721.