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Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response
Jaya Sangodkar, … , Analisa DiFeo, Goutham Narla
Jaya Sangodkar, … , Analisa DiFeo, Goutham Narla
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(7):2637-2651. https://doi.org/10.1172/JCI62058.
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Research Article Oncology

Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response

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Abstract

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 activation of AKT signaling. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR–based therapies, 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. We identified a transcriptional network involving the tumor suppressors Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma. Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR–based therapy for the treatment of metastatic lung adenocarcinoma.

Authors

Jaya Sangodkar, Neil S. Dhawan, Heather Melville, Varan J. Singh, Eric Yuan, Huma Rana, Sudeh Izadmehr, Caroline Farrington, Sahar Mazhar, Suzanna Katz, Tara Albano, Pearlann Arnovitz, Rachel Okrent, Michael Ohlmeyer, Matthew Galsky, David Burstein, David Zhang, Katerina Politi, Analisa DiFeo, Goutham Narla

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Figure 3

Activated RAS signaling does not affect KLF6 expression.

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Activated RAS signaling does not affect KLF6 expression.
(A) Western blo...
(A) Western blot of lung tissue lysates extracted and microdissected from transgenic KrasLA2 mice to exclude obvious tumor nodules versus lung tissue lysates of WT littermates. Tumor nodules were excluded to ensure that any changes in KLF6 were not secondary to tumor formation. Western blot shows p-ERK, ERK, and KLF6 protein expression normalized to mouse tubulin. (B) p-ERK to ERK ratios determined by quantitating protein expression from A. (C) qRT-PCR of KLF6 expression in lung tissue lysates of KrasLA2 mice versus WT littermates performed as previously described. For B and C, whiskers represent the range of expression, while the horizontal line shows the median. (D) Western blot for p-ERK, ERK, KLF6, and GAPDH in the HCC827 cell line treated with 1 μM of the MEK inhibitor AZD6244. (E) qRT-PCR for KLF6 in the HCC827 cell line treated with 1 μM AZD6244, normalized to GAPDH. ***P < 0.001.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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