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Abstract

ERK hyperactivation is a novel vulnerability in lung adenocarcinoma based on killing tumor cells by over activating the ERK/MAPK signaling pathway. While activation of this pathway is typically associated with the malignant phenotype, research has revealed that tumors still depend on tight regulation of ERK/MAPK signaling intensity and are sensitive to both insufficient and excessive signaling. ERK hyperactivation provides a strong negative selection pressure in lung adenocarcinoma, as is evidenced by the mutual exclusivity and synthetic lethality of oncogenic mutations in EGFR and KRAS. However, the signaling vulnerabilities underpinning ERK induced lethality and the clinical relevance remain unclear. To investigate the molecular mechanisms of ERK induced toxicity, I used transcriptional data paired with functional genomics data and identified proteotoxic stress as vulnerability to cells undergoing ERK hyperactivation. Through a limited drug screen, I found that the N-linked glycosylation inhibitor tunicamycin increased sensitivity to ERK hyperactivation. To study ERK hyperactivation in a clinically relevant setting, I generated models of resistance to drugs used for the treatment of lung adenocarcinoma. In a model of trametinib resistance, I found that KRASG12C amplification resulted in a “drug addicted” phenotype, whereby trametinib removal caused ERK hyperactivation lethal to cells. In models of osimertinib resistance, I profiled the potential of multiple genes to induce ERK hyperactivation. I also demonstrated that tunicamycin potentiated ERK hyperactivation induced by overexpression of oncogenes, inhibition of ERK/MAPK negative regulators or drug removal in models of drug resistance. Overall, this thesis explores the molecular mechanisms underpinning ERK induced lethality and demonstrates the potential to harness this dependency in a clinical setting.