Project Abstract
Lung cancer is the number one cause of cancer death in the United States. Non-small cell lung cancer
(NSCLC), which accounts for the majority (80%) of lung cancer diagnoses, is divided into two major sub-types,
lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LUSC). New therapeutic strategies targeting
major oncogenic drivers of LADC have led to improved response rates and patient survival. However, due to a
lack of well-characterized, validated, and therapeutically-actionable oncogenic drivers, similar therapeutic
advances for LUSC have not been forthcoming. Genomic analysis of primary human LUSC reveals that the
most prevalent recurrent genetic alterations in LUSC are concurrent loss of TP53 and copy number gains
(CNGs) at chromosome 3q26 (>85-90%). These genetic alterations are observed in both precancerous lesions
and early-stage LUSC, indicating they are early promotive events in LUSC tumorigenesis. Our previous studies
have demonstrated that the 3q26 genes, PRKCI, SOX2 and ECT2 are coordinately co-amplified and
functionally collaborate to maintain the transformed phenotype of LUSC cells. PKCι, the protein product for
PRKCI, directly phosphorylates and regulates the oncogenic function of SOX2 and ECT2 in LUSC cells.
Furthermore, our preliminary data demonstrate that: 1) overexpression of SOX2, PRKCI and ECT2, in the
context of Trp53 loss, is sufficient to transform mouse lung basal stem cells (LBSCs), a major cell of origin for
LUSC, and drive formation of tumors with malignant LUSC characteristics; 2) PKCι-SOX2 signaling activates a
master transcriptional program specifying lineage-restricted lung squamous transformation; 3) PKCι-ECT2
signaling functions to increase the proliferative potential of LUSC cells through control of MEK-ERK signaling
and enhanced ribosome biogenesis; and 4) both human LUSC cell lines with 3q26 CNGs and SOX2, PRKCI
and ECT2 transformed LBSCs are sensitive to the growth inhibitory effects of Auranofin (ANF), a potent
PKCι inhibitor, and to small molecule inhibitors of oncogenic PKCι-SOX2 and PKCι-ECT2 driven effector
pathways including Hedgehog, WNT, NOTCH, MEK-ERK and rRNA synthesis. Based on these data we
hypothesize that: 1) PRKCI, SOX2 and ECT2 represent cooperative multigenic drivers of LUSC
tumorigenesis; and 2) combined treatment with ANF and inhibitors of PKCι-SOX2 and PKCι-ECT2
effector pathways will synergistically inhibit transformed growth of LUSC tumors. These hypotheses will
be tested through completion of two interrelated specific aims designed to: 1) evaluate the efficacy of novel
drug combinations that target oncogenic PKCι effector pathways; and 2) characterize a novel genetically-
tractable mouse model for PRKCI-driven LUSC. Successful completion of these studies will facilitate the
design of novel therapeutic strategies to improve outcomes for patients with LUSC. Furthermore, our novel
clinically-relevant genetically-engineered LUSC mouse model will enhance our understanding of LUSC biology,
characterize LUSC initiation and progression from preneoplastic lesions to malignant LUSC, identify markers
for early LUSC diagnosis and develop and test novel targeted therapies for improved treatment of LUSC.