JAK2 Signaling Mediates Immune Evasion and PIK3CA Inhibitor Resistance in Ovarian Cancer 2953
Year: 2025
Type: article
Abstract: Description High-grade serous ovarian cancer (HGSOC) is the dominant histologic subtype diagnosed clinically and accounts for 70–80% of deaths of ovarian cancer. Alterations of PI3KCA (encoding PI3Ka), including mutation, amplification or overexpression, occur in 20∼50% of HGSOC patient samples. While the PI3Ka inhibitor alpelisib has been approved for PIK3CA-mutated breast cancer, it showed limited efficacy as monotherapy in HGSOC. Using syngeneic genetically engineered mouse models (GEMMs) of HGSOC and patient-derived xenografts with hyperactivation of PI3Kα, we demonstrated that PI3Kα inhibitor treatment induces activation of the JAK2 signaling pathway in tumor cells and enhances the infiltration of pro-tumor macrophages into the tumor microenvironment. This process may contribute to the recurrence and progression of PI3Kα-hyperactivated tumors following treatment. Our preclinical data suggest that either JAK2 pathway inhibition or STING agonist treatment may enhance the therapeutic efficacy of PI3Kα inhibitors and overcome resistance in HGSOC. Our study aims to elucidate the mechanism of PI3Kα inhibitor-induced immunosuppression and therapeutic resistance, potentially leading to improved treatment strategy for PI3Kα-hyperactivated HGSOC. Funding Sources This study is supported in part by NIH/NCI MERIT Award R37 CA279440, R35 CA210057 and P01 CA269021. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Source: The Journal of Immunology
Authors: Liya Ding, Michael Kearns, Jean Zhao
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416447134
FWCI:
Cites:
Cited by:
Related to: