Dissertation/Thesis Abstract

The Role of KLF6 Gene in Lung Cancer
by Sangodkar, Jaya, Ph.D., Icahn School of Medicine at Mount Sinai, 2012, 144; 3553575
Abstract (Summary)

Lung cancer is the leading cause of cancer related death in the United States and the high mortality rate associated with lung cancer has prompted efforts in understanding the molecular origins of the disease. Epidermal growth factor receptor (EGFR) activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms including constitutive activation of AKT signaling. Additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. Here I identify a transcriptional network involving the KLF6 and FOXO1 tumor suppressor genes that negatively regulate activated EGFR signaling and that can be reactivated using the combination of two FDA approved agents in both cell culture and in vivo models of the disease. In both murine models and patient derived lung adenocarcinoma samples, EGFR activation is associated with FOXO1 mislocalization and decreased KLF6 expression. Furthermore, in a Kras driven mouse model, KLF6 expression is not significantly changed whereas AKT activation seen in the Pten/Mmac1+/- heterozygous mouse model results in FOXO1 mislocalization and decreased KLF6 expression. Consistent with these findings, inhibition of AKT signaling promotes increase in nuclear FOXO1 resulting in transactivation of the KLF6 tumor suppressor gene in lung adenocarcinoma cell lines. Correspondingly, the EGFRL858R mouse model demonstrates spontaneous tumor regression when treated with the anti-EGFR based therapy, erlotinib, an FDA-approved small-molecule inhibitor of EGFR signaling. I analyzed L858R mouse tumors samples treated with erlotinib and found increased KLF6 expression following EGFR inhibition. Conversely, targeted reduction of KLF6 resulted in decreased erlotinib response in both cell culture and in vivo models of disease suggesting a direct link between KLF6 upregulation and the induction of apoptosis by anti-EGFR based therapy. Therefore, I hypothesized that acquired resistance to anti-EGFR based therapies could be overcome by restoring downstream function of the FOXO1/KLF6 transcriptional network. Here I demonstrate that an FDA-approved drug, trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restores sensitivity to AKT-driven erlotinib-resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models. Furthermore, silencing of FOXO1 blunts apoptosis mediated through combination erlotinib and TFP treatment suggesting that this transcriptional network is important for negatively regulating AKT signaling. Combined, these studies define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs with the potential for rapid clinical translation to restore chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma.

Furthermore the alternative splice variant of the KLF6 tumor suppressor gene, KLF6-SV1, has been shown to be associated with decreased survival in patients with lung adenocarcinoma. Here I demonstrate that lung cancer cells that are chemoresistant express increased levels of KLF6-SV1 and targeted reduction of KLF6-SV1 using RNA interference restores chemosensitivity both in culture and in vivo. These findings highlight a role for KLF6-SV1 in regulation of chemotherapy response.

Indexing (document details)
Advisor: Narla, Goutham
Commitee: Cagan, Ross, Cobrinik, David, Friedman, Scott, O'Connell, Matthew, Yu, Qin
School: Icahn School of Medicine at Mount Sinai
Department: Cancer Biology
School Location: United States -- New York
Source: DAI-B 74/06(E), Dissertation Abstracts International
Subjects: Molecular biology, Genetics, Cellular biology, Oncology
Keywords: Egfr, Foxo1, Klf6 gene, Lung cancer, Nsclc
Publication Number: 3553575
ISBN: 9781267930637