Abstract A017: Deciphering the role of integrated stress response (ISR) in the developmental stages of mutant KRAS lung cancer

Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) constitutes 80% of all lung malignancies with 15-25% attributed to mutations in the KRAS gene. KRAS mutations expose cells to stress-inducing conditions, e.g., genotoxic, proteotoxic and metabolic stress, which disrupt normal proliferation and tissue homeostasis. Successful proliferation of tumors is dependent on stress-adaptive pathways, which promote growth and contribute to resistance to chemotherapeutic drugs. Thus, inhibition of the adaptation process is considered a suitable anti-tumor approach for the treatment of KRAS cancers including lung cancer. An important mechanism of adaptation to stress involves the phosphorylation of the translation initiation factor eIF2α at serine 52 (p-eIF2α). Increased p-eIF2α is the nodal point of the integrated stress response (ISR), a master regulator of translational and transcriptional reprogramming that determines survival and adaptation to stress. We demonstrated the tumorigenic function of p-eIF2α in a mouse model of mutant KRAS cancer (Nature Communications 2021). We delineate the role of the ISR in lineage diversity and tumor heterogeneity during KRAS LUAD progression by single-cell RNA sequencing (sc-RNA seq). As such, the ISR was found to drive high stemness and epithelial to mesenchymal transition (EMT) programs in KRAS LUAD cells. The ISR also employs a high-plasticity cell-state mechanism for successful lung tumor progression and evolution. The involvement of the ISR in the mentioned processes further emphasizes its role as master regulator of pro-tumorigenic pathways and highlights the therapeutic potential of ISR inhibitors as novel targets in KRAS lung cancer. Our recent findings demonstrate that increased p-eIF2α stimulates the activity of the gene trans-activator proteins YAP and TAZ in mutant KRAS lung tumors. Genetic approaches identify a stimulatory effect of p-eIF2 on the expression of YAP/TAZ-dependent genes with roles in proliferation and epithelial to mesenchymal transition (EMT) including genes of WNT signaling pathway. We provide strong evidence that stimulation of YAP/TAZ activity by p-eIF2α occurs, at least partially, through the upregulation of the transcription factor ATF4 in tumor cells. Our findings demonstrate that p-eIF2α is a focal point of different tumorigenic pathways, intimately implicated in mutant KRAS-mediated transformation and tumor resistance to mutant KRAS inactivation. Citation Format: Shiqi Diao, Nour Ghaddar, Jia Yi Zou, Shuo Wang, Antonis E. Koromilas. Deciphering the role of integrated stress response (ISR) in the developmental stages of mutant KRAS lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A017.