GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer

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 greater dependency of these cells on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here we conducted CRISPR/Cas9 knockout screens to identify genes influencing the response of SCLC cells to WEE1 kinase inhibition. These screens uncovered a role for the GCN2 amino acid-sensing pathway in modulating the response of SCLC cells to WEE1 inhibition. Rapid activation of GCN2 upon WEE1 inhibition triggers a stress response. Pharmacological activation of the GCN2 pathway synergizes with WEE1 inhibition. Thus, activation of the GCN2 amino acid-sensing pathway represents a novel approach for augmenting the efficacy of WEE1 inhibitors in SCLC.