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

Jacob A Herman1, Romario R Romain1, Pia Hoellerbauer2

  • 1Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523.

Proceedings of the National Academy of Sciences of the United States of America
|October 3, 2022
PubMed

Insights

Cancer cells with RAS or MAPK signaling are vulnerable to BubR1 inhibition. This vulnerability arises because these pathways disrupt chromosome segregation, increasing reliance on BubR1 for maintaining the spindle assembly checkpoint and error correction.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Genetics

Background:

  • Aneuploidy, an abnormal chromosome number, is prevalent in tumors and drives their development.
  • Kinetochores are crucial protein complexes that ensure accurate chromosome segregation during cell division.
  • BubR1 is vital for kinetochore function, acting in both error correction and the spindle assembly checkpoint (SAC), and is a cancer therapeutic target.

Purpose of the Study:

  • To investigate the oncogenic pressures driving cancer-specific dependency on BubR1.
  • To determine if BubR1's role in the SAC or error correction underlies this dependency.
  • To identify the molecular mechanisms linking oncogenic signaling to BubR1 vulnerability.

Main Methods:

  • Utilized a genetically controlled transformation model.
  • Analyzed glioblastoma tumor isolates.
  • Investigated the impact of RAS and MAPK signaling on kinetochore function and chromosome segregation.

Main Results:

  • Constitutive RAS or MAPK signaling is essential for the cancer-specific vulnerability to BubR1 inhibition.
  • The MAPK pathway hyperstimulates kinetochore kinases, impairing chromosome segregation.
  • This impairment increases cellular dependence on BubR1 for error correction and SAC maintenance.

Conclusions:

  • RAS/MAPK signaling creates a dependency on BubR1 by compromising chromosome segregation.
  • BubR1's dual roles in error correction and SAC are critical for cancer cells under oncogenic stress.
  • This study reveals an oncogenic trigger for a cancer-specific defect in chromosome segregation.
Keywords:
BubR1MAPKaneuploidykinetochoremitosis

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