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Genetic and drug perturbation of components in the NFkB signaling pathway in 11-18 cells

ABSTRACT: Through the study of EGFR-mutant lung adenocarcinoma we show that NFkB signaling is rapidly engaged by EGFR oncogene inhibition to promote tumor cell persistence and therapy resistance. Unexpectedly, we found that EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NFkB-mediated transcriptional survival program. We identified a direct pharmacologic NFkB inhibitor, PBS-1086, that suppressed this adaptive survival program and increased both the magnitude and duration of initial EGFR TKI response in cellular and in vivo tumor models, including a novel patient-derived NSCLC xenograft. These findings unveil NFkB as a critical adaptive survival mechanism engaged in response to EGFR oncogene inhibition and identify PBS-1086 as a promising NFkB inhibitor to eliminate disease persistence and potentially prevent the emergence of resistance in patients. RNAseq analysis of 11-18 (EGFR-mutant lung adenocarcinoma) cells in the context of drug treatment with erlotinib and/or genetic or pharmacological inactivation of NFkB

ORGANISM(S): Homo sapiens

SUBMITTER: Saurabh Asthana

PROVIDER: E-GEOD-65420 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genetic and drug perturbation of components in the NFkB signaling pathway in 11-18 cells

Project description:Through the study of EGFR-mutant lung adenocarcinoma we show that NFkB signaling is rapidly engaged by EGFR oncogene inhibition to promote tumor cell persistence and therapy resistance. Unexpectedly, we found that EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NFkB-mediated transcriptional survival program. We identified a direct pharmacologic NFkB inhibitor, PBS-1086, that suppressed this adaptive survival program and increased both the magnitude and duration of initial EGFR TKI response in cellular and in vivo tumor models, including a novel patient-derived NSCLC xenograft. These findings unveil NFkB as a critical adaptive survival mechanism engaged in response to EGFR oncogene inhibition and identify PBS-1086 as a promising NFkB inhibitor to eliminate disease persistence and potentially prevent the emergence of resistance in patients.

2015-02-03 | GSE65420 | GEO

TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

Project description:Adenocarcinoma is the most common histologic subtype of lung cancer, which is the leading cause of cancer death. We and others previously identified TTF-1, a lineage-specific transcription factor required for branching morphogenesis and physiological lung functions, as a lineage-survival oncogene in lung adenocarcinoma. However, how TTF-1 mediates survival signals remains elusive. Here we show that TTF-1 induces receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn mediates TTF-1 survival signaling in lung adenocarcinoma. Inhibition of ROR1 impaired prosurvival signaling through the PI3K-AKT pathway and induced nuclear accumulation of FOXO1. These were found to be imposed, at least in part, through PTEN inactivation via c-Src, while ROR1 was shown to physically interact with and phosphorylate c-Src. ROR1 inhibition also elicited marked p38 activation, provoking ill-balance between prosurvival and proapoptotic signaling, and consequential “oncogenic shock.” In addition, we found that ROR1 is crucially involved in EGFR- and MET-mediated prosurvival signaling. ROR1 knockdown effectively induced apoptosis in lung adenocarcinoma cell lines with acquired EGFR TKI resistance conferred by a secondary T790M EGFR mutation, or HGF-elicited MET signaling and resultant switching of the addicted receptor tyrosine kinases (RTKs). Taken together, our findings indicate that ROR1 RTK is a very promising molecular target for development of a novel therapeutic means to treat this hard-to-cure cancer. Dye-swap experiment, vector control vs. stable TTF-1 transfectant of HPL1D, immortalized human peripheral lung epithelial cell line.

2011-12-31 | E-GEOD-25830 | biostudies-arrayexpress

TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

2011-12-31 | GSE25830 | GEO

Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

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Global transcriptional profiling of HCC827 lung adenocarcinoma cells in response to EGFR inhibition

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Effect of a dual specificity PI3K/mTOR inhibitor, NVP-BEZ235, on human ovarian cancer cell lines grown in 3D culture

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2012-03-13 | E-GEOD-28992 | biostudies-arrayexpress

Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: H3122

Project description:ALK and ROS1 fusions defines subsets of lung adenocarcinoma. Although ALK/ROS1 inhibitors improved therapeutic outcome of patients harboring those oncogenic fusions, complete responses were rare, and resistance eventually develops from the residual tumor. To under the mechanisms contributing to residual tumor formation, we performed phosphoproteomics to explore the signaling adaption shortly after ALK/ROS1 inhibition. We found the phosphorylation of Mig6, a potent inhibitor for EGFR, was decreased following ALK/ROS1 inhibition, impairing Mig6 binding and inhibition on EGFR. Furthermore, Mig6 mRNA and protein levels were decreased rapidly by ALK/ROS1 inhibitors, potentiating EGFR activity to support cell survival. We also uncovered a novel mechanism mediated by Mig6 to regulate EGFR activity without impacting EGFR phosphorylation, but rather altering signaling adaptor SHC1 binding to EGFR. Mig6 expression was also lost following long-term exposure to ALK/ROS1 inhibitors to support EGFR-mediated acquired resistance. Finally, a Mig6 EGFR-binding domain truncation mutation was identified in a patient-derived ROS1 cell line, rendering its resistance to ROS1 inhibitors but sensitivity to HER family inhibitors. Our work established a rationale to evaluate combinations of ALK/ROS1 and EGFR inhibitors to limit residual tumor formation, therefore preventing or delaying subsequent resistance emergence.

2023-09-12 | PXD036772 | Pride

Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: Cuto28

2023-09-12 | PXD036771 | Pride

Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway [scRNASeq]

Project description:Eradicating tumor dormancy that develops following oncogene-targeted therapy, including after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer (NSCLC), is an attractive therapeutic strategy but the mechanisms governing the establishment of tumor dormancy are poorly understood. We observe that blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state, characterized by extensive epigenetic remodeling and high YAP/TEAD activity. YAP/TEAD trigger an epithelial-to-mesenchymal transition (EMT) program and engage the EMT transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP or TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK induced apoptosis. Thus, YAP activation can promote the survival of EGFR-mutant NSCLC cells in the chronic absence of EGFR signaling. Eradicating this population enhances the efficacy of targeted therapies which could ultimately lead to prolonged treatment responses in cancer patients.

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Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway [DMSO vs DORMANT]

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