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Updated: Feb 7, 2026
Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
Published on: July 30, 2020
Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A
Abstract:
Targeted therapies eliminate cancer cells by inhibiting oncogenic signaling; however, tumor cells often evade cytotoxicity through proteomic and epigenetic reprogramming that enables survival. These adaptive responses may create collateral cellular stresses, such as DNA damage, that can be therapeutically exploited. When unresolved, DNA damage leads to chromosomal instability (CIN), a potential source of vulnerability. Whether KRAS inhibition induces DNA damage or CIN in KRAS -mutant non-small cell lung cancer (NSCLC) has not been established. Here, we show that the KRAS G12C inhibitor LY3499446 induces CIN in KRAS -mutant NSCLC cell lines. A targeted compound screen revealed that the extent of CIN induction by KRAS G12C inhibition strongly correlates with therapeutic synergy with the selective Aurora kinase A inhibitor LSN3321213. Mechanistically, KRAS G12C inhibition stabilizes cyclin B1 during mitosis through activation of mitotic ATR/ATM signaling. In the presence of Aurora Kinase A inhibition, cyclin B1 stabilization delays mitotic exit and diverts cell fate from mitotic slippage or division toward mitotic catastrophe. Together, our findings identify CIN as a predictive marker of response to combined KRAS G12C and Aurora Kinase A inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies.
Insights
KRAS inhibition causes chromosomal instability (CIN) in KRAS-mutant lung cancer. Combining KRAS and Aurora Kinase A inhibitors shows therapeutic synergy, with CIN predicting treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Targeted therapies face resistance from cancer cell adaptation.
- Tumor cells may develop vulnerabilities like DNA damage and chromosomal instability (CIN) upon treatment.
- The impact of KRAS inhibition on DNA damage and CIN in KRAS-mutant non-small cell lung cancer (NSCLC) is unknown.
Purpose of the Study:
- To investigate if KRAS inhibition induces DNA damage and CIN in KRAS-mutant NSCLC.
- To identify potential therapeutic strategies that exploit KRAS inhibition-induced vulnerabilities.
- To explore the synergistic potential of combining KRAS inhibition with other targeted agents.
Main Methods:
- Treatment of KRAS-mutant NSCLC cell lines with KRAS G12C inhibitor LY3499446.
- Assessment of chromosomal instability (CIN) induction.
- Compound screening to identify synergistic drug combinations.
- Mechanistic studies involving mitotic signaling pathways (ATR/ATM) and cyclin B1 stabilization.
Main Results:
- KRAS G12C inhibition with LY3499446 induced CIN in KRAS-mutant NSCLC cells.
- The degree of CIN induction correlated with synergistic efficacy when combined with Aurora Kinase A inhibitor LSN3321213.
- KRAS G12C inhibition stabilized cyclin B1 via mitotic ATR/ATM signaling.
- Combined inhibition led to delayed mitotic exit and mitotic catastrophe, bypassing slippage or division.
Conclusions:
- Chromosomal instability (CIN) is induced by KRAS G12C inhibition in NSCLC.
- CIN serves as a predictive biomarker for response to combined KRAS G12C and Aurora Kinase A inhibition.
- This combination strategy offers a rationale for enhancing therapeutic outcomes in KRAS-mutant NSCLC.
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