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51.
Shigeru Kawabata M Christine Hollander Jeeva P. Munasinghe Lauren R. Brinster José R. Mercado-Matos Jie Li Lucia Regales William Pao Pasi A. J?nne Kwok-Kin Wong John A. Butman Russell R. Lonser Marlan R. Hansen Richard K. Gurgel Alexander O. Vortmeyer Phillip A. Dennis 《Oncotarget》2015,6(13):11357-11368
Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms. 相似文献
52.
Katherine E. Hutchinson Douglas B. Johnson Adam S. Johnson Violeta Sanchez Maria Kuba Pengcheng Lu Xi Chen Mark C. Kelley Qingguo Wang Zhongming Zhao Mark Kris Michael F. Berger Jeffrey A. Sosman William Pao 《Oncotarget》2015,6(26):22348-22360
Melanomas are characterized by activating “driver” mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative (“pan-negative”) patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease. 相似文献
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54.
Monica Red Brewer Cai-Hong Yun Darson Lai Mark A. Lemmon Michael J. Eck William Pao 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(38):E3595-E3604
The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a “donor” tyrosine kinase domain (TKD) contacts an “acceptor” TKD, leading to its activation. In the context of a ligand-induced dimer, identical wild-type EGFR TKDs are thought to assume the donor or acceptor roles in a random manner. Here, we present biochemical reconstitution data demonstrating that activated EGFR mutants found in lung cancer preferentially assume the acceptor role when coexpressed with WT EGFR. Mutated EGFRs show enhanced association with WT EGFR, leading to hyperphosphorylation of the WT counterpart. Mutated EGFRs also hyperphosphorylate the related erythroblastic leukemia viral oncogene (ErbB) family member, ErbB-2, in a similar manner. This directional “superacceptor activity” is particularly pronounced in the drug-resistant L834R/T766M mutant. A 4-Å crystal structure of this mutant in the active conformation reveals an asymmetric dimer interface that is essentially the same as that in WT EGFR. Asymmetric dimer formation induces an allosteric conformational change in the acceptor subunit. Thus, superacceptor activity likely arises simply from a lower energetic cost associated with this conformational change in the mutant EGFR compared with WT, rather than from any structural alteration that impairs the donor role of the mutant. Collectively, these findings define a previously unrecognized mode of mutant-specific intermolecular regulation for ErbB receptors, knowledge of which could potentially be exploited for therapeutic benefit.The gene encoding the epidermal growth factor receptor (EGFR) tyrosine kinase is somatically mutated in a substantial fraction of patients with lung cancer. The majority of primary activating EGFR mutations occur within the tyrosine kinase domain (TKD). The most frequent of these, which occur with a combined frequency of 90% (1), are exon 19 deletions that eliminate four amino acids (LREA) from the TKD and exon 21 missense mutations that substitute arginine for leucine at position 834 (L834R) (also identified as L858R in an alternative numbering of the human EGFR sequence that includes the 24 residue signal sequence) (2).Exon 19 deletions and L834R substitutions are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, translating to a 70% radiographic response rate in patients (3–5). Unfortunately, all individuals with metastatic disease eventually develop progressive disease after 10–16 mo of treatment with EGFR TKIs. The most common mechanism of acquired resistance is mutation at a second site in the EGFR TKD (the gatekeeper residue), T766M (T790M). This mutation confers resistance by increasing affinity for ATP, with which inhibitors must compete for binding, and also by modestly decreasing intrinsic affinity for TKIs (6).Biochemical and crystallographic studies have shown that activation of the wild-type (WT) EGFR TKD involves formation of an asymmetric dimer in which one molecule allosterically activates its neighbor by promoting the reversal of intramolecular autoinhibitory interactions—acting as a “donor” or “activator” TKD that activates the “acceptor” or “receiver” TKD (7, 8). Crystal structures of individual L834R and T766M EGFR-TKD mutants show that these variants also form asymmetric dimers (6, 9), but whether the double mutant L834R/T766M adheres to the same configuration in the active state is unclear. Biochemical data indicate that the oligomerization potential of mutated EGFRs is enhanced relative to WT. For example, native gel and multiangle light scattering studies showed that the L834R substitution promotes formation of dimers and higher order oligomers of the EGFR TKD (10). Consistent with this observation, cell-based studies have demonstrated a reduced dependence on ligand stimulation for activation of mutated EGFRs. All mutated EGFR TKDs seen in lung cancer show an increase in catalytic efficiency over WT (6, 9, 11, 12). Interestingly, the doubly mutated L834R/T766M EGFR TKD has a two-to fivefold higher catalytic efficiency (kcat/Km) than either the singly mutated L834R or T766M mutant TKDs (6).Here, using a biochemical and structural approach, we sought to determine whether mutated EGFRs most commonly associated with primary drug sensitivity and acquired resistance in lung cancer adhere to the well-established asymmetric dimer model. Our biochemical reconstitution data demonstrate that these EGFR mutations do in fact adhere to this model, but with the striking difference that the oncogenic mutants preferentially assume the receiver role when expressed together with WT EGFR. Our crystal structure of active EGFR-L834R/T766M reveals an asymmetric dimer interface essentially the same as that in WT EGFR. We further show that mutated EGFRs can hyperphosphorylate WT EGFR as well as the related family member erythroblastic leukemia viral oncogene (ErbB)2 as a result of their preferential adoption of the acceptor or receiver position in the asymmetric dimer. These findings have important implications for understanding mechanisms of drug sensitivity and resistance in EGFR mutant lung cancers and shed light on the distinct properties of different mutated forms of EGFR. 相似文献
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56.
57.
Effect of apical root resorption on periodontal support 总被引:1,自引:0,他引:1
58.
Y. F. Shi X. Xie C. L. Zhao D. F. Ye S. M. Lu J. J. Hor C. C. Pao 《British journal of cancer》1996,73(10):1216-1219
The objectives of this study were to better our understanding of the carcinogenesis of gestational trophoblastic tumours and to investigate the possible presence of mutational alteration of the p53 tumour-suppressor gene in these tumours. Amplification-based direct DNA sequencing was performed on 14 hydatidiform moles, six invasive moles, eight choriocarcinomas and ten normal early placental tissues. No mutation in exons 5-8 was detected in any of these 38 tissue specimens. These results suggest that a mutation in p53 tumour suppressor either does not exist or is a very rare event in gestational trophoblastic tumours. The gestational trophoblastic tumours probably involve a tumour-suppressor gene other than p53 gene or may follow a completely different pathway to their malignant phenotype. 相似文献
59.
Analysis of peripheral blood of pregnant women for the presence of fetal Y chromosome-specific ZFY gene deoxyribonucleic acid sequences. 总被引:6,自引:0,他引:6
S M Kao G C Tang T T Hsieh K C Young H C Wang C C Pao 《American journal of obstetrics and gynecology》1992,166(3):1013-1019
Deoxyribonucleic acid sequences of human ZFY (zinc-finger-Y) gene, a Y-chromosome-specific gene and candidate for the testis-determining factor, has been identified by an in vitro enzymatic deoxyribonucleic acid amplification method in peripheral blood specimens of women pregnant with male fetuses. This technique permits detection of ZFY gene deoxyribonucleic acid sequences in as few as a single male cell among 1,000,000 female cells. Maternal blood results were confirmed by amplification of ZFY gene deoxyribonucleic acid sequences in chorionic villus cells and by karyotyping in 33 of 36 pregnant women. There was no false-positive male result, and two of the three blood specimens with false-negative results were obtained from pregnant women at a very early gestational age. With properly designed guidelines, this deoxyribonucleic acid amplification method may be an alternative to determine the fetal sex for those pregnancies at risk for X-linked genetic disorders. 相似文献
60.
Dietary patterns of women smokers and non-smokers 总被引:5,自引:1,他引:4
F A Larkin P P Basiotis H A Riddick K E Sykes E M Pao 《Journal of the American Dietetic Association》1990,90(2):230-237
The 1-day food intakes of 1,338 women, aged 19 to 50, who were respondents in the 1985 Continuing Survey of Food Intake by Individuals, were studied. The energy, nutrient, and food intake patterns of smokers, those how had quit smoking, and those who had never smoked cigarettes were compared. Mean energy intakes of smokers (1,627 kcal), those who had never smoked (1,620 kcal), and those who had quit at least 1 year before the interview (1,719 kcal) were not significantly different. Self-reported body weight was significantly different between never-smokers and smokers (p less than .01) and quitters (p less than .05) only for the oldest category of women (ages 41 to 50 years). The consumption of fruits (p less than .001) and vegetables (p less than .01) was significantly lower and the intake of eggs (p less than .01), sugars (p less than .001), regular carbonated soft drinks (p less than .01), coffee (p less than .001), and alcoholic beverages (p less than .001) was significantly higher for women smokers than for non-smokers. After controlling through regression analysis for physical activity, health status, and demographic characteristics, we found that smokers, compared with never-smokers, had significantly lower protein (p less than .04), dietary fiber (p less than .001), vitamin C (p less than .001), and thiamin (p less than .01) intakes and higher cholesterol (p less than .02) intakes per 1,000 kcal. 相似文献