Induction of lung adenocarcinoma in transgenic mice expressing activated <i>EGFR</i> driven by the SP‐C promoter

Ohashi, Kadoaki; Rai, Kammei; Fujiwara, Yoshiro; Osawa, Masahiro; Hirano, Satoshi; Takata, Katsuyoshi; Kondo, Eisaku; Yoshino, Tadashi; Takata, Minoru; Tanimoto, Mitsune; Kiura, Katsuyuki

doi:10.1111/j.1349-7006.2008.00875.x

Cited by 26 publications

(26 citation statements)

References 40 publications

(50 reference statements)

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“…2A). We previously reported that no interstitial lung disease was found in the mice treated with gefitinib (29) and no other toxicities of skin, intestine, and liver developed in this study (Supplementary Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

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Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

Ninomiya

Takigawa

Ichihara

et al. 2013

Molecular Cancer Therapeutics

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An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P ¼ 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation. Mol Cancer Ther; 12(5); 589-97. Ó2013 AACR.

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Section: Resultsmentioning

confidence: 99%

“…The transgenic mice had no distant metastases (29,30). All animals were kept under pathogen-free conditions with abundant food and water as specified in the guidelines of the Department of Animal Resources, Okayama University Advanced Science Research Center, Okayama, Japan.…”

Section: Animal Husbandry and Drug Treatmentmentioning

confidence: 99%

Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

Ninomiya

Takigawa

Ichihara

et al. 2013

Molecular Cancer Therapeutics

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“…21 However, Ohashi et al reported that transgenic mice expressing the delE748-A752 mutant version of mouse EGFR driven by the SP-C promoter developed multifocal lung adenocarcinomas with the AAH and BAC (lepidic) pattern at 3-5 weeks of age. 25 Others also concluded that the mutations are early, pre-invasive changes, whereas copy number gains are later events associated with the invasive phenotype. 23,24 In the present study, the micro-dissected BAC (lepidic) pattern was thought to correspond to a pre-invasive tumor lesion: EGFR mutations were more common, though not significantly, in the BAC (lepidic) pattern.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma

Tomonaga

Nakamura

Yamaguchi

et al. 2013

Clinical Lung Cancer

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2 Micro abstractIntra-tumor heterogeneity of epidermal growth factor receptor (EGFR) mutations in patients with mixed-type lung adenocarcinoma was analyzed according to histological patterns. Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and there was a significant correlation between heterogeneity of EGFR mutations and smoking history (P<0.043). Clinical Practice Points• EGFR mutations are factors predictive of response to EGFR-TKI treatment. However, lung cancer is thought to be the result of the accumulation of genetic alterations over a long course of exposure to a carcinogen, and the existence of intra-tumor heterogeneity of EGFR mutations remains unclear. Thus, the existence of intra-tumor heterogeneity was analyzed in patients with mixed-type lung adenocarcinoma according to histological patterns.• Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and a significant correlation between heterogeneity of EGFR 3 mutations and smoking history was found.• Response to EGFR-TKIs might be partial and insufficient in tumors having intra-tumor heterogeneity of EGFR mutations. New treatment strategies for patients with lung adenocarcinoma harboring heterogeneous EGFR mutations are needed.

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“…We generated transgenic mice expressing the delE748-A752 mutant of mouse Egfr, which is equivalent to the delE746-A750 mutant (10). The transgenic mice used the SP-C promoter to express mutated Egfr in type II alveolar cells.…”

Section: Transgenic Mouse Modelmentioning

confidence: 99%

“…We established transgenic mice expressing the delE748-A752 mutant of mouse Egfr, which corresponded to the delE746-A750 mutant of human EGFR (10). In the transgenic mice, pSTAT3 was overexpressed in the bronchioloalveolar carcinoma component around the adenocarcinoma center (11).…”

Section: Introductionmentioning

confidence: 99%

Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model

et al. 2014

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Disclosure of potential conflicts of interest: N. Takigawa and K. Kiura: Honoraria from speakers bureau, AstraZeneca. The other authors disclosed no potential conflicts of interest.Word count: 3498; total number of figures and tables: 5; supplemental figure: 1 ABSTRACT STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. Three EGFR tyrosine kinase inhibitor-resistant cell lines, RPC-9, PC-9/Van-R, and PC-9/ER3, were established from PC-9 harboring an EGFR exon19 deletion mutation. Their resistance mechanisms were caused mainly by a secondary mutation of T790M (RPC-9, PC-9/Van-R) or JAK2 activation (PC-9/ER3). Both resistant and parent cells were sensitive to AZD1480. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model using PC-9 cells. Subsequently, the transgenic mice expressing Egfr delE748-A752 were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1 mm) in the AZD1480-treated group and control group were 0.37 ± 0.18 and 2.25 ± 0.53 (p<0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, and pJAK2. To evaluate the efficacy of AZD1480 on survival, AZD1480 (n=13) or vehicle (n=13) was administered orally from 7 weeks of age. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p<0.0001). In conclusion, AZD1480 may be effective against lung tumors driven by an activating EGFR mutation.

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Induction of lung adenocarcinoma in transgenic mice expressing activated EGFR driven by the SP‐C promoter

Cited by 26 publications

References 40 publications

Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma

Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model

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