ABSTRACT PKC ISOZYMES IN LUNG CANCER DEVELOPMENT AND THERAPY RESISTANCE Mahlet B. Abera Marcelo G. Kazanietz, Ph.D. Non-small cell lung cancer (NSCLC) is one of the major causes of cancer related mortality worldwide and comprises the most frequent type of lung cancers. Oncogenic alterations such as activating mutations in the epidermal growth factor receptor (EGFR) and KRAS have been implicated in the pathogenesis of NSCLC. Protein kinase C (PKC), a family of serine/threonine kinases that are targets of phorbol ester/diacylglycerol, has been shown to be involved in EGFR and KRAS signaling, indicating their importance in lung cancer progression. In this thesis work, we established the requirement of PKCα and PKCε in the malignancy of lung cancer in the context of EGFR and KRAS mutations. Using an isogenic model system, we found NSCLC cells that are resistant to the EGFR-tyrosine kinase inhibitor erlotinib display remarkably high levels of PKCα compared to the parental erlotinib sensitive cells. Inhibition of PKCα resulted in sensitization to erlotinib treatment and loss of gene expression associated with mesenchymal phenotype. Additionally, we showed that PKCα signaling controls activation of a key regulator of lung cancer progression, NF-κΒ. PKCα depletion by RNA interference in lung cancer cells indeed attenuates IκΒα phosphorylation, subsequent impairment of NF-κΒ translocation into the nucleus, and induction of NF-κΒ target genes in response to interleukin 1 beta (IL-1β). Finally, in the context of KRAS mutation, we presented evidence showing the requirement of PKCε signaling for the formation of KRAS-driven lung tumors in vivo. Tumor formation in the double transgenic KRASG12D;PKCε-/- mice was remarkably reduced compared to KRASG12D;PKCε+/+ mice. All together, this thesis work highlights the multiple roles that PKC isozymes play in the initiation and progression of lung cancer, and suggests a potential therapeutic role for PKCα and PKCε inhibitors for prevention and treatment of lung tumors.