Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A

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.