NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma

Yamaguchi, Tomoya; Yanagisawa, Kiyoshi; Sugiyama, Ryoji; Hosono, Yasuyuki; Shimada, Yukako; Arima, Chinatsu; Kato, Seiichi; Tomida, Shuta; Suzuki, Motoshi; Osada, Hiroyuki; Takahashi, Takashi

doi:10.1016/j.ccr.2012.02.008

Cited by 219 publications

(287 citation statements)

References 47 publications

(65 reference statements)

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“…Our study also sought to understand how integrin b1 promotes Akt phosphorylation and the acquisition of drug resistance. Of the potentially relevant molecules, Src is known to be a downstream regulator of EGFR and/or integrins and it plays an essential role in the survival of lung cancer cells (35,36). Src is also responsible for the acquisition of resistance to EGFR-targeted drugs (37,38).…”

Section: Discussionmentioning

confidence: 99%

Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling

et al. 2013

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EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin b1, a2, and a5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin b1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin b1, a5, and/or a2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin b1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs. Cancer Res; 73(20); 6243-53. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling

et al. 2013

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“…The potential oncogenic role of NKX2-1 in the pathogenesis of adenocarcinoma of the lung was proposed by findings that a region of 14q13.3 containing NKX2-1, NKX2-8, and PAX9 was amplified in approximately 10% of human lung adenocarcinoma (5)(6)(7). Loss-offunction and gain-of-function studies in human lung carcinoma and transformed cells supported a role of NKX2-1 as an oncogene (5)(6)(7)(8)(9); however, the Kras LSL-G12D/+ ;p53 -/-mouse model and a xenograft mouse model supported the concept that NKX2-1 is an antimetastatic factor (10,11).…”

Section: Introductionmentioning

confidence: 98%

KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

Maeda

Tsuchiya

Hao³

et al. 2012

J. Clin. Invest.

141

198

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Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras G12D , but not with oncogenic EGFR L858R , caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells. Expression of NKX2-1 inhibited urethane and oncogenic Kras G12D -induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced Kras G12D -mediated tumor progression, but reduced EGFR L858R -mediated progression. Genome-wide analysis of gene expression demonstrated that a set of genes induced in mucinous tumors was shared with genes induced in a nontumorigenic chronic lung disease, while a distinct subset of genes was specific to mucinous tumors. ChIP with massively parallel DNA sequencing identified a direct association of NKX2-1 with the genes induced in mucinous tumors. NKX2-1 associated with the AP-1 binding element as well as the canonical NKX2-1 binding element. NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras G12D -driven mucinous pulmonary adenocarcinoma. IntroductionMucinous adenocarcinoma of the lung (formerly known as mucinous bronchioalveolar cancer) is pathologically classified as tumor cells with goblet cell morphology containing abundant intracytoplasmic mucin (1). Invasive mucinous adenocarcinoma of the lung has a higher malignant potential than do the more common types of lung adenocarcinoma, such as acinar or papillary adenocarcinoma. Mucinous adenocarcinoma of the lung is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1) and the expression of mucins, including mucin 5AC, oligomeric mucus/gel-forming (MUC5AC). Genetically, approximately 76% of mucinous adenocarcinomas of the lung have KRAS mutations, a frequent mutation in lung adenocarcinoma associated with tobacco use (2), but mucinous adenocarcinoma of the lung is rarely associated with EGFR mutations. In contrast, nonmucinous lung adenocarcinoma is frequently associated with EGFR mutations (∼45%), but less frequently with KRAS mutations (∼13%; ref. 1).NKX2-1 plays a critical role in lung morphogenesis and respiratory epithelial-specific gene expression, including activation of surfactant proteins and repression of mucins (3, 4). The potential oncogenic role of NKX2-1 in the pathogenesis of adenocarcinoma of the lung was proposed by findings that a region of 14q13.3 containing NKX2-1, NKX2-8, and PAX9 was amplified in approximately 10% of human lung adenocarcinoma (5-7). Loss-offunction and gain-of-function studies in human lung carcinoma and transformed cells supporte...

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“…On the other hand, ROR2 also can repress transcription of Wnt target genes and modulate Wnt signaling by sequestering canonical Wnt ligands, thereby serving as a tumor suppressor in different cell contexts (27,28). Although studies have shown that ROR1 or ROR2 can associate with other proteins to modify canonical Wnt signaling or induce noncanonical signaling (29,30), ROR1 and ROR2 are each considered to function independently of one another. We examined primary CLL cells for ROR1-associated proteins and made the unexpected discovery that ROR1 formed heterooligomers with ROR2 in response to Wnt5a to recruit guanine exchange factors (GEFs) that activate Rho GTPases, which can enhance leukemiacell chemotaxis and proliferation.…”

Section: Introductionmentioning

confidence: 99%

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

Yu¹,

Chen²,

Cui³

et al. 2015

Journal of Clinical Investigation

159

215

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NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma

Cited by 219 publications

References 47 publications

Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling

Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling

KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

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