Mutant EGFR (mEGFR) is a key driver of a subset of lung adenocarcinoma that is targetable by specific inhibitors; however, responses are transient, and patients almost always relapse, thus necessitating a deep understanding of the mechanisms involved in the action of mEGFR. Our studies are leading to the discovery of rewiring of EGFR signaling in mEGFR with a pivotal role played by protein kinase C (PKC). We find that patients with tumors having mEGFR often show a selection for very high levels of PKC?, and these patients have substantially worse prognosis, further underscoring the need to study PKC. We find that this enhanced expression of PKC results in its sustained activation which then results in the activation of Akt, mTOR, and other downstream targets. This proposal will focus on developing and testing the hypothesis that cancers with mEGFR require independent selection for high expression and sustained activation of PKC? which then plays a key role in allowing oncogenic signaling and growth by mEGFR. We will pursue the following specific aims: Aim 1. Define the sustained activation of PKC? in response to mEGFR and the role of PKC? in mediating key signaling functions of mEGFR and elucidate key mechanisms. We will establish the activation of PKC? and define its roles in mediating the activation of Akt and mTOR in mEGFR cells and determine if and how the induction of cPKC? switches signaling downstream of mEGFR. We will also define the mechanisms involved. Aim 2. Define the role of PKC? in mediating oncogenic responses to mEGFR. Here will evaluate the hypothesis that hyper-activation of PKC? in mEGFR lung cancers mediates critical oncogenic properties in cells and in vivo. Taken together, these results are beginning to define a novel coordinated pathway of oncogenesis in those cancers that become addicted to the PKC pathway. Moreover, these novel results may constitute a paradigm shift in our understanding of mechanisms regulating PKC and its significance to cancer biology and therapeutics, especially in preventing emergence of resistance to EGFR inhibitors.