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Published on: January 7, 2019
Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer
Athea Vichas1, Amanda K Riley1,2, Naomi T Nkinsi1
1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Abstract:
CRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.
Insights
Researchers mapped cancer dependencies for the RIT1 oncogene, revealing unique vulnerabilities in RIT1-mutant lung cancer. This identifies potential therapeutic targets, including the spindle assembly checkpoint and YAP1 pathway.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- CRISPR-based cancer dependency maps are crucial for precision medicine but are limited to common oncogenes.
- Rarity of functional maps hinders therapeutic development for less common cancer subsets.
Purpose of the Study:
- Investigate oncogene-specific dependencies conferred by the RIT1 oncogene in lung cancer.
- Identify therapeutic intervention opportunities in RIT1-mutant lung cancer.
Main Methods:
- Genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells.
- Small-molecule sensitivity profiling.
- Analysis of spindle assembly checkpoint regulators and YAP1 pathway interactions.
Main Results:
- Identified shared and unique vulnerabilities across KRAS, EGFR, and RIT1-mutant lung cancer cells.
- RIT1-mutant cells exhibit unique sensitivity to loss of spindle assembly checkpoint regulators.
- Oncogenic RIT1 weakens the spindle assembly checkpoint, causing sensitivity to Aurora A inhibition.
- Observed synergy between mutant RIT1 and YAP1 activation, with frequent nuclear YAP1 overexpression in RIT1-mutant tumors.
Conclusions:
- Provided a genome-wide atlas of oncogenic RIT1 functional interactions.
- Identified RAS pathway components, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets for RIT1-mutant lung cancer.
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