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GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer
Alexandros P Drainas1, Wen-Hao Hsu1, Alec E Dallas1
1Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Abstract:
Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a dependency on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M checkpoint kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here, using CRISPR-Cas9 knockout screens in vitro and in vivo, we identified multiple factors influencing the response of SCLC cells to the WEE1 kinase inhibitor AZD1775, including the GCN2 kinase and other members of its signaling pathway. Rapid activation of GCN2 upon AZD1775 treatment triggers a stress response in SCLC cells. Pharmacological or genetic activation of the GCN2 pathway enhances cancer cell killing by AZD1775. Thus, activation of the GCN2 pathway represents a promising strategy to increase the efficacy of WEE1 inhibitors in SCLC.
Insights
Targeting the G2/M checkpoint kinase WEE1 shows promise for small-cell lung cancer (SCLC). Activating the GCN2 pathway enhances cancer cell killing by WEE1 inhibitors, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Small-cell lung cancer (SCLC) lacks effective treatments.
- SCLC cells rely on the G2/M checkpoint for survival due to G1 checkpoint failures.
- WEE1 kinase inhibitors show preclinical promise but face toxicity and resistance issues.
Purpose of the Study:
- To identify factors influencing SCLC response to the WEE1 inhibitor AZD1775.
- To explore strategies for overcoming resistance and enhancing WEE1 inhibitor efficacy in SCLC.
Main Methods:
- Utilized CRISPR-Cas9 knockout screens in vitro and in vivo.
- Investigated the role of GCN2 kinase and its signaling pathway.
- Assessed the impact of GCN2 pathway activation on SCLC cell killing by AZD1775.
Main Results:
- Identified GCN2 kinase and its pathway as key modulators of AZD1775 response in SCLC.
- Observed rapid GCN2 activation upon AZD1775 treatment, inducing a cellular stress response.
- Demonstrated that pharmacological or genetic activation of GCN2 enhances AZD1775-mediated cancer cell death.
Conclusions:
- Activation of the GCN2 pathway is a promising strategy to improve WEE1 inhibitor efficacy in SCLC.
- Targeting GCN2 may overcome resistance and reduce toxicity associated with WEE1 inhibition in SCLC treatment.
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