Role of JAK inhibition in quiescent cancer cells and their microenvironment

Recurrent breast cancer is typically incurable and arises from the reservoir of residual tumor cells (RTCs) that can persist for decades in patients in a dormant state after primary tumor treatment. Although tumor dormancy and recurrence are responsible for the vast majority of breast cancer deaths, their mechanisms are poorly understood. In this regard, JAK-STAT signaling is activated in many human cancers and exerts a variety of pro-tumorigenic effects. Strikingly, using validated genetically engineered mouse (GEM) models that faithfully recapitulate breast cancer dormancy and recurrence in patients, we have made the surprising discovery that JAK1 deletion or pharmacological inhibition accelerates breast cancer recurrence by inducing RTCs to exit the dormant state and resume proliferation. Based on these findings, we hypothesize that JAK1/2 signaling is required to suppresses breast cancer recurrence and that it does so by enforcing a dormant state in RTCs. If true, this would raise the concerning possibility that administration of JAK1/2 inhibitors to patients harboring dormant RTCs could inadvertently trigger reentry of tumor cells into the cell cycle, which could ultimately result in lethal recurrence. Indeed, we have recently found that breast cancer patients exposed to a JAK inhibitor at some point after their initial diagnosis have a significantly increased risk of recurrence. Since there are >4 million breast cancer survivors in the U.S., and millions of patients treated with JAK inhibitors for a wide array of chronic inflammatory conditions, the possibility that JAK inhibition might increase recurrence risk when administered to early-stage cancer patients with dormant MRD is critical to evaluate. The specific aims of this proposal are to: (1) Determine the contribution of host immunity to dormancy exit and tumor recurrence caused by JAK1/2 inhibition using genetic and pharmacological approaches in GEM models, and (2) Identify the mechanisms by which JAK1/2 inhibition affects dormancy and tumor recurrence by examining the role of STAT proteins, JAK kinase activity, and cell cycle regulators using in vitro and in vivo GEM models. Because we hypothesize that JAK inhibitors may be harmful when given to breast cancer survivors, we must use model systems to test this hypothesis. The mouse has been chosen as a model for our studies both because of the similarity of its mammary gland to humans and because it permits us to accurately model biological variables in patients critical to dormancy and recurrence, such as the immune system and tumor microenvironment. Elucidating the pathways that enforce tumor dormancy and contribute to recurrence is a critical priority for cancer patients. By expanding our understanding of the mechanisms by which dormant RTCs survive and recur, this project has the potential to inform therapeutic approaches in patients who harbor dormant MRD following treatment of their primary cancer. Ultimately, the abilities to therapeutically target escape pathways used by dormant RTCs, while avoiding iatrogenic activation of RTCs that would otherwise remain dormant, has the potential to prevent recurrence, thereby providing new treatment options for millions of cancer survivors. Project Number: 1R01CA312067-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: LEWIS CHODOSH | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $523,544 | Activity Code: R01 | Study Section: Tumor Host Interactions Study Section[THI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11347480