Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities.

in Proceedings of the National Academy of Sciences of the United States of America by Jacob A Herman, Romario R Romain, Pia Hoellerbauer, Hazheen K Shirnekhi, David C King, Keith F DeLuca, Erin Osborne Nishimura, Patrick J Paddison, Jennifer G DeLuca

TLDR

  • The study found that a protein called BubR1 is more important for cancer cells to grow and survive than for normal cells. The study also found that a protein called RAS or MAPK makes BubR1 more important for cancer cells to grow and survive. The study suggests that targeting BubR1 could be a way to treat cancer.

Abstract

Aneuploidy, the incorrect number of whole chromosomes, is a common feature of tumors that contributes to their initiation and evolution. Preventing aneuploidy requires properly functioning kinetochores, which are large protein complexes assembled on centromeric DNA that link mitotic chromosomes to dynamic spindle microtubules and facilitate chromosome segregation. The kinetochore leverages at least two mechanisms to prevent aneuploidy: error correction and the spindle assembly checkpoint (SAC). BubR1, a factor involved in both processes, was identified as a cancer dependency and therapeutic target in multiple tumor types; however, it remains unclear what specific oncogenic pressures drive this enhanced dependency on BubR1 and whether it arises from BubR1's regulation of the SAC or error-correction pathways. Here, we use a genetically controlled transformation model and glioblastoma tumor isolates to show that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The MAPK pathway enzymatically hyperstimulates a network of kinetochore kinases that compromises chromosome segregation, rendering cells more dependent on two BubR1 activities: counteracting excessive kinetochore-microtubule turnover for error correction and maintaining the SAC. This work expands our understanding of how chromosome segregation adapts to different cellular states and reveals an oncogenic trigger of a cancer-specific defect.

Overview

  • The study focuses on aneuploidy, a common feature of tumors, and the role of kinetochores in preventing it. The hypothesis being tested is that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The methodology used includes a genetically controlled transformation model and glioblastoma tumor isolates. The primary objective of the study is to understand how chromosome segregation adapts to different cellular states and reveal an oncogenic trigger of a cancer-specific defect.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically constitutive signaling by RAS or MAPK. The results show that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The key findings of the study reveal that the MAPK pathway enzymatically hyperstimulates a network of kinetochore kinases that compromises chromosome segregation, rendering cells more dependent on two BubR1 activities: counteracting excessive kinetochore-microtubule turnover for error correction and maintaining the spindle assembly checkpoint. These findings suggest that targeting BubR1 may be a promising therapeutic approach for cancer treatment.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies constitutive signaling by RAS or MAPK as a necessary condition for cancer-specific BubR1 vulnerability, which could lead to the development of new therapeutic targets for cancer treatment. The study also reveals the oncogenic trigger of a cancer-specific defect, which could help in understanding the underlying mechanisms of cancer development and progression. Future research directions could include further investigation of the role of BubR1 in cancer and the development of targeted therapies that specifically target BubR1.
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