Abstract Chromosome segregation fidelity relies on stable attachments between kinetochores (KTs) and spindle microtubules during mitosis. We recently identified a previously unrecognized form of KT dysfunction that is prevalent in human glioblastoma (GBM) isolates and is triggered by aberrant activation of mitogen-activated protein kinase (MAPK) signaling during mitosis. This phenotype—termed MAPK-stressed kinetochores (MaSKs)—arises when hyperactive Ras-Raf-MEK-ERK signaling drives excessive phosphorylation of KT components by a network of KT-associated kinases. As a result, MT-binding affinity is reduced and KT-MT turnover becomes abnormally high, producing a lethal mitotic stress state. MaSKs provide a direct mechanistic link between oncogenic Ras/MAPK pathway activity and the generation of chromosome instability, filling a key gap in our understanding of how mitogenic oncogenes disrupt mitosis. Notably, MaSKs appear to be restricted to cancer and transformed cells, where they create unique genetic and molecular dependencies. MaSK-positive cells rely specifically on two non-essential domains of the mitotic checkpoint protein BubR1/BUB1B to recruit PP2A phosphatase and suppress MaSK-induced KT-MT instability. These dependencies suggest new opportunities for tumor-selective therapeutic targeting. In this presentation, we will describe the molecular basis of MaSK formation, the assays enabling their discovery, and evidence supporting their utility as biomarkers for a subset of MAPK-driven tumors. We further discuss how MaSKs can be exploited to identify novel therapeutic strategies and define a patient responder population. Citation Format: Jennifer DeLuca, Patrick J. Paddison. MAPK driven kinetochore instability as a biomarker and therapeutic vulnerability in glioblastoma 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 2979.
DeLuca et al. (2026) studied this question.