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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 1077-1077
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 11619-11619
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 11619-11619
    Abstract: 11619 Background: AR is expressed in the majority of BCs and its signaling may contribute to the development of BC metastases (mets). The expression pattern of AR, its phosphorylated form, p-AR S650, and correlations with other BC growth and survival pathways were evaluated in BC mets by reverse phase protein array (RPPA). Methods: RPPA was performed on 93 FFPE primary BCs and mets at a CLIA-certified laboratory. Immunostaining with 24 antibodies was directed against AR, p-AR S650, p-MET, and total and p-HER1/2/3 pathway proteins. Clinical and genomic data were obtained from pt chart review. Analysis of variance (ANOVA) was used to assess any statistically significant differences between the groups. Results: 35 tissues were primary BCs (38%); 58 were mets (62%). Sites of mets: liver (n = 41); lung (n = 8); chest wall (n = 9). Of the 41 liver mets, 2 were triple negative (TN), 32 were ER+/HER2-, and 7 were HER2+. AR expression was increased in chest wall (1.7-fold; p = 0.038) compared to primary BCs. p-AR was increased in liver (2.0-fold; p = 0.039) and chest wall (1.8-fold; p = 0.026) compared to primary BCs. ER+ liver mets especially showed strong liver-specific activation of AR along with overexpression of HER1, HER3, VEGFR, and activation of mTOR, S6 Ribo, 4EBP1, and STAT3. MEK/ERK pathway was not activated in ER+ liver mets. HER2+ liver mets had pan-HER1/2/3 activation along with MET, SRC, S6 Ribo, 4EBP1, and JAK2/STAT3. In the 2 TN liver mets, EGFR, VEGFR, mTOR, S6 Ribo, 4EBP1, and JAK2/STAT3 were activated while AR and MEK/ERK were not. The ER+ liver mets showed higher expression of p-AR (p = 0.079), p-HER3 (p = 0.002), p-HER2 (p = 0.010) and p-Jak2 (p = 0.002) compared to primary ER+ BCs whereas the HER2+ liver mets showed lower level of p-IGFR (p = 0.049) and p-MET (p = 0.010) compared to primary HER2+ BCs. Interestingly, TN chest wall mets had higher levels of AR and p-AR (p = 0.008 and 0.044 respectively) compared to TN BCs. Conclusions: ER+ liver mets have strong expression of AR and p-AR, and all liver met subtypes showed accumulation of S6 Ribo/4EBP1 and activation of JAK2/STAT3, but not the MAPK pathway. HER1/3 and HER1/2/3 were activated in ER+ and HER2+ liver mets, respectively. These data suggest that targeting AR, HER1/3, and mTOR in ER+ liver met would be of interest.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 5_suppl ( 2012-02-10), p. 434-434
    Abstract: 434 Background: There are marked differences in responses to therapy among patients with clear cell renal cell carcinoma (ccRCC), which makes the outcome difficult to predict. This study is aimed to define a new classification system that would elucidate distinctions between carcinomas in order to facilitate selection of the appropriate treatment. We mapped cell signaling pathways in individual renal cell carcinomas and identified different classes based on commonly shared phosphorylation-driven signaling networks. Methods: Laser capture microdissection and reverse-phase protein arrays were used to profile 75 key nodes in 16 primary clear cell renal cancers. These nodes represent many signaling pathways known to be important in tumorigenesis and progression. Results: Statistical analysis revealed significant differences (p 〈 0.05) in signaling levels between two groups of samples, group A (4 samples) and group B (12 samples), for 27 of the 75 endpoints tested. In group A, high activation levels of EGFR, RET, and RASGFR1 converged to activate AKT/mTOR. Group B, showed high phosphorylation levels of ERK1/2 and STAT transcription factors and samples significantly partitioned in two clusters of 7 and 5 cases designated C and D. Group C showed elevated expression of a regulator of autophagy, LC3B; group D showed activation of Src and STAT transcription factors, suggesting the presence of cytokine-mediated cell survival pathways. A DNA copy number analysis was performed on the same samples and the results showed that group B represents some paradigmatic cases of ccRCC, with VHL loss-of-function mutations. Conclusions: The proteins identified appeared to be linked to pathways that are targeted by drugs typically used to treat clear cell renal cell carcinoma. Thus, this type of analysis could be useful for stratifying patients and selecting the best therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 34 ( 2015-12-01), p. 4023-4031
    Abstract: To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600–mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600–mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response 〉 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study 〉 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft–bearing mice and the biopsied lesions from each corresponding patient. Conclusion The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600–mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 4_suppl ( 2016-02-01), p. TPS773-TPS773
    Abstract: TPS773 Background: Treatment with Regorafenib (REGO) has shown significant clinical benefits in metastatic colorectal cancer (mCRC) patients (pts) as demonstrated in the CORRECT and CONCUR trials. Results from both studies suggest that subgroups have differential responses. Further research to identify these subgroups through the identification of molecular biomarkers is needed. Methods: Forty pts with refractory mCRC are being enrolled in this study. The primary objective is to prospectively identify tissue and serum-based biomarkers that can predict response to REGO. Secondary objectives are to determine molecular mechanisms by which REGO controls refractory mCRC, as well as molecular pathways involved in the acquisition of resistance. Tumor and blood samples are obtained prior to and 2 weeks after starting REGO. Blood samples are collected on day 1 of each cycle thereafter. Pts will receive 160 mg REGO daily for 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Multi-omic based biomarker discovery approaches will be used to uncover predictive marker candidates with special attention to the tumor microenvironment. Laser capture microdissection will be used on tumor tissue to procure highly enriched populations of pt-matched epithelial and stromal/immune cell infiltrates. Each of these entities will be analyzed for RNA expression changes and protein signaling/drug target activation mapping. Protein signaling analysis will be performed by reverse phase protein array of key REGO-related proteins and phosphoproteins (e.g. phosphoVEGFR, Tie2, phosphoRET), as well as broad-scale mapping of mitogenic, survival, autophagy, inflammatory, motility, and signaling networks. Tumor profiling will include next-generation sequencing for 592 genes with 53 selected gene fusions, and IHC and FISH/CISH for selected biomarkers, including PDL1, HER2, MSI, TS, ERCC1, and TOPO1. Blood samples will undergo protein, miRNA, and mutated DNA analysis, as well as exosomal signature study via a proprietary synthetic polyligand multiplexed aptamer-based assay. Exploratory analysis of biomarkers will be used to determine correlations between the presence of, or change in, biomarker levels and clinical response. Clinical trial information: NCT01949194.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 6
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 1 ( 2020-01-01), p. 54-71
    Abstract: Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line– and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. Significance: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents. See related commentary by Klempner and Hata, p. 20. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2607892-2
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  • 7
    In: JAMA Network Open, American Medical Association (AMA), Vol. 6, No. 9 ( 2023-09-14), p. e2333618-
    Abstract: Breast cancer mortality is complex and traditional approaches that seek to identify determinants of mortality assume that their effects on mortality are stationary across geographic space and scales. Objective To identify geographic variation in the associations of population demographics, environmental, lifestyle, and health care access with breast cancer mortality at the US county-level. Design, Setting, and Participants This geospatial cross-sectional study used data from the Surveillance, Epidemiology, and End Results (SEER) database on adult female patients with breast cancer. Statistical and spatial analysis was completed using adjusted mortality rates from 2015 to 2019 for 2176 counties in the US. Data were analyzed July 2022. Exposures County-level population demographics, environmental, lifestyle, and health care access variables were obtained from open data sources. Main Outcomes and Measures Model coefficients describing the association between 18 variables and age-adjusted breast cancer mortality rate. Compared with a multivariable linear regression (OLS), multiscale geographically weighted regression (MGWR) relaxed the assumption of spatial stationarity and allowed for the magnitude, direction, and significance of coefficients to change across geographic space. Results Both OLS and MGWR models agreed that county-level age-adjusted breast cancer mortality rates were significantly positively associated with obesity (OLS: β, 1.21; 95% CI, 0.88 to 1.54; mean [SD] MGWR: β, 0.72 [0.02] ) and negatively associated with proportion of adults screened via mammograms (OLS: β, −1.27; 95% CI, −1.70 to −0.84; mean [SD] MGWR: β, −1.07 [0.16] ). Furthermore, the MGWR model revealed that these 2 determinants were associated with a stationary effect on mortality across the US. However, the MGWR model provided important insights on other county-level factors differentially associated with breast cancer mortality across the US. Both models agreed that smoking (OLS: β, −0.65; 95% CI, −0.98 to −0.32; mean [SD] MGWR: β, −0.75 [0.92] ), food environment index (OLS: β, −1.35; 95% CI, −1.72 to −0.98; mean [SD] MGWR: β, −1.69 [0.70] ), exercise opportunities (OLS: β, −0.56; 95% CI, −0.91 to −0.21; mean [SD] MGWR: β, −0.59 [0.81] ), racial segregation (OLS: β, −0.60; 95% CI, −0.89 to −0.31; mean [SD] MGWR: β, −0.47 [0.41] ), mental health care physician ratio (OLS: β, −0.93; 95% CI, −1.44 to −0.42; mean [SD] MGWR: β, −0.48 [0.92] ), and primary care physician ratio (OLS: β, −1.46; 95% CI, −2.13 to −0.79; mean [SD] MGWR: β, −1.06 [0.57] ) were negatively associated with breast cancer mortality, and that light pollution was positively associated (OLS: β, 0.48; 95% CI, 0.24 to 0.72; mean [SD] MGWR: β, 0.27 [0.04] ). But in the MGWR model, the magnitude of effect sizes and significance varied across geographical regions. Inversely, the OLS model found that disability was not a significant variable for breast cancer mortality, yet the MGWR model found that it was significantly positively associated in some geographical locations. Conclusions and Relevance This cross-sectional study found that not all social determinants associated with breast cancer mortality are spatially stationary and provides spatially explicit insights for public health practitioners to guide geographically targeted interventions.
    Type of Medium: Online Resource
    ISSN: 2574-3805
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    detail.hit.zdb_id: 2931249-8
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  • 8
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 1 ( 2022-01-01), p. 114-126
    Abstract: In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resistance and with poor long-term outcomes in the p53-mutated sonic hedgehog, MYC-p53, and p53-positive medulloblastoma subgroups. We previously established a direct role for p53 in supporting drug resistance in medulloblastoma cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in medulloblastoma cells with low basal p53 protein expression levels (D283 and UW228) significantly reduced drug responsiveness, suggesting opposing roles for low p53 protein expression levels. Mechanistically, the enhanced cell death by p53 knockdown in high-p53 cells was associated with an induction of mTOR/PI3K signaling. Both mTOR inhibition and p110α/PIK3CA induction confirmed these findings, which abrogated or accentuated the enhanced chemosensitivity response in D556 cells respectively while converse was seen in D283 cells. Co-treatment with G-actin–sequestering peptide, thymosin β4 (Tβ4), induced p-AKTS473 in both p53-high and p53-low cells, enhancing chemosensitivity in D556 cells while enhancing chemoresistance in D283 and UW228 cells. Implications: Collectively, we identified an unexpected role for the PI3K signaling in enhancing cell death in medulloblastoma cells with high basal p53 expression. These studies indicate that levels of p53 immunopositivity may serve as a diagnostic marker of chemotherapy resistance and for defining therapeutic targeting.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-287-LB-287
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal five-year survival rate of just eight percent in the advanced metastatic setting. Outcomes with standard chemotherapy regimens are less than ideal; therefore, the development of targeted therapies for the treatment of PDAC is a significant unmet clinical need. The two most frequent genetic events in PDAC (mutational activation of KRAS and loss of the tumor suppressor CDKN2A) converge on activation of the kinases CDK4 and CDK6, which promote G1 cell cycle progression. While clinically relevant agents directly targeting KRAS in PDAC remain elusive, pharmacologic restoration of CDKN2A function by inhibition of CDK4/6 may be an effective anti-KRAS therapeutic strategy. Supporting this hypothesis, we found that CDK4/6 inhibitors (e.g., palbociclib, abemaciclib, lerociclib) elicited single-agent activity in a subset of tested PDAC cell lines. However, using Reverse Phase Protein Array (RPPA), we observed widespread compensatory changes that overcome CDK4/6 inhibition, including increased anti-apoptotic protein expression, PI3K-mTOR and ERK MAPK signaling. Concurrent treatment with the potent and selective ERK1/2 inhibitor (ERKi) SCH772984 reversed resistance and increased sensitivity to palbociclib. This combination caused synergistic reduction in anchorage-dependent cell growth, and increased apoptosis, G1 arrest, and senescence. In an organoid model of pancreatic cancer, cell viability was synergistically reduced and caspase activation enhanced. We have also evaluated the combination of ERKi with palbociclib or the clinical-stage CDK4/6 inhibitor lerociclib (G1T38) in mouse models of PDAC, supporting our initiation of a phase Ib clinical trial of the ERK inhibitor ulixertinib/BVD-523 in combination with palbociclib in advanced metastatic pancreatic cancer (NCT03454035). Next, we sought to identify additional genes that regulate sensitivity to CDK4/6 inhibition. Using a CRISPR/Cas9 loss-of-function screen, we individually silenced expression of 2500 genes from the “druggable genome” in combination with palbociclib in six KRAS-mutant pancreatic and two KRAS-mutant colorectal cancer cell lines. We identified a wide array of genes that enhanced growth suppression in combination, centered around diverse signaling nodes including PI3K-AKT-mTOR signaling, cell cycle regulation and mitosis, SRC family kinase signaling, cell metabolism and biosynthesis, chromosome regulation and maintenance, and DNA damage & repair pathways, suggesting novel small molecule combinations to overcome de novo or acquired CDK4/6 inhibitor resistance in the clinic. We also identified genes whose loss imparts a survival advantage, suggesting possible resistance mechanisms to single-agent CDK4/6 inhibition. In total, these data suggest that CDK4/6 inhibitors alone, or in combination, may benefit PDAC patients clinically. Citation Format: Craig M. Goodwin, Sehrish Javaid, Andrew M. Waters, Bjoern Papke, Runying Yang, Mariaelena Pierobon, Daniel M. Freed, Patrick J. Roberts, Adrienne D. Cox, Kris C. Wood, Emanuel F. Petricoin, Autumn J. McRee, Channing J. Der. Combination therapies with CDK4/6 inhibitors to treat KRAS-mutant pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-287.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2254-2254
    Abstract: Background: Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, characterizing ~80% of lung cancer diagnoses. Thus, the development of novel therapies for NSCLC is of primary importance in oncology. The aim of this study was to develop a novel cancer systems biology approach to understand the complex interactions in NSCLC and predict the response to target treatments. We combined proteomic experimental data with a machine learning tool to discover the diverse signaling networks of both KRAS mutant (MUT) and wild-type (WT) NSCLC cell lines (CL). Material and Methods: Eight NSCLC CL (5 KRAS MUT and 3 KRAS WT) were subjected to reverse phase protein microarray (RPPA) to explore the activation level of 183 proteins treated with selumetinib (SE) and its combination with everolimus (EV) or tamoxifen (TA). Measures were taken at 6 time points: 5 minutes (min), 1, 2 , 6 and 24 hours (h). RPPA was performed also on the baseline and on CL with only dimethyl sulfoxide. Recursive Feature Elimination with Support Vector Machine (RFE-SVM) was used to identify the subset of proteins/features that optimally separated samples in 2 groups. In order to build the interaction network from this subset and browse the main pathways involved, we used Reactome FI and the Pathway Enrichment tool, two Cytoscape plugins for network-based data analysis. Results: We applied RFE-SVM to discover the most divergent proteins between control and treated samples in the whole CL panel. For all the 3 drug combinations, the network in output contained not only the target of the corresponding drug, but also showed the activation of other parallel pathways. The analysis revealed also that all drugs were mainly effective in a short time, since the number of significant proteins was considerably higher at 5 min and 1 h. For instance, SE treatment activated NGFR, mTOR, PI3K-Akt and proteoglycans pathways in addition to the MAPK pathway. Network at 1 h contained 25 proteins linked by 76 interactions, while at 6 and 24 h the distinctive subsets of features included only 2 and 4 proteins. Then, we applied RFE-SVM to analyze KRAS MUT vs WT CLs. The algorithm showed that treated KRAS MUT CL had a more complex signaling network than the WT ones. Indeed, in SE WT samples MER and ERK were the main relevant proteins to distinguish from the control. In treated KRAS MUT samples, a complex network of 70 proteins and 278 interactions was active during the first hour. Conclusion: The proposed framework processes high-throughput data and identifies new possible molecular targets in cancer research. This approach is highly flexible for a multitude of data and purposes. We applied it to a RPPA dataset of NSCLC CL and it revealed that all drug combinations had fast dynamics and that KRAS MUT CL had a more complicated response due to a higher number of active pathways. Citation Format: Chiara Antonini, Lorenzo Tomassoni, Elisa Baldelli, Vienna Ludovini, Sara Baglivo, Mariaelena Pierobon, Emanuel F Petricoin, Lucio Crinò, Paolo Valigi, Fortunato Bianconi. Dynamic network topologies analysis in proteomics data of NSCLC cell lines using a new pipeline based on machine learning tools [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2254.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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