Abstract 2264 Role of atypical Mitogen-Activated Protein Kinase 15 (MAPK15) in ovarian cancer cell survival and metastasis

Atypical protein kinases, which lack conventional regulatory domains, play critical roles in pathophysiology by modulating signaling pathways involved in cell proliferation and survival, often contributing to tumor progression and therapy resistance.However, significant knowledge gaps remain regarding their context-specific functions, regulatory mechanisms, noncatalytic roles, and therapeutic potential.MAPK15, an atypical MAPK capable of autophosphorylation in the absence of upstream kinases and regulated by an elongated C-terminal domain, is emerging as a key player in cancer.Our study aimed to elucidate its regulation and impact in cancer metastasis.Anchorage-independent survival, essential for metastasis, enables cancer cells to survive detachment from the primary tumor and colonize distant sites.Through unbiased transcriptomics across five cancer cell lines in attached and suspension conditions, we identified MAPK15 as significantly upregulated in suspension.Analysis of TCGA data revealed MAPK15 expression to be elevated in tumors, correlating with poor survival, particularly in ovarian cancer.We confirmed MAPK15 induction at both mRNA and protein levels within six hours of matrix detachment, accompanied by TEY phosphorylation, indicating activation.Cycloheximide treatment demonstrated that MAPK15 expression in suspension is translation dependent.Furthermore, MAPK15 was highly expressed in high-grade serous carcinoma (HGSC) cell lines, the most aggressive ovarian cancer subtype.Functional studies with MAPK15 overexpression (OE) and knockdown in ovarian cancer models revealed that MAPK15 OE enhanced viability, spheroid size, and invasion in suspension, while knockdown reduced viability and spheroid formation.Mechanistically, MAPK15 OE supported survival by increasing proliferation and reducing caspase-3-mediated cell death in detached conditions.Our findings highlight MAPK15 as a translationally regulated driver of anchorage-independent survival, critical for metastasis.Ongoing studies on kinase-dead (D154A) and Cterminal deletion mutants will further delineate the roles of kinase activity and the C-terminal domain in this process, with data to be presented.