bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2685: Paracrine effect of NRG1 and HGF drives resistance to MEK inhibitors in metastatic uveal melanoma
Authors: Cheng Hanyin , Terai Mizue , Sato Takami , Aplin Andrew 
Published: August 2015

Abstract
Metastatic uveal melanoma (UM) patients usually die within one year, emphasizing an urgent need to develop new treatment strategies. Mitogen-activated protein kinase kinase (MEK) small molecule inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in UM patients. In this study, we identified compensatory mechanisms that provide resistance to MEK inhibition in metastatic UM. We screened for growth factors that were able to induce resistance in three newly characterized metastatic UM cell lines to MEK inhibitors, trametinib and selumetinib, with colony formation assay and viability assay. Cellular signaling pathway analysis was carried out to determine the molecular mechanisms of resistance to MEK inhibition in metastatic UM cells. Clinical-grade antibody and inhibitors targeting these pathways were used to determine their capability to overcome the resistance mediated by these growth factors. Conditioned medium collected from fibroblasts were used to evaluate whether stromal effect from fibroblasts could drive resistance to metastatic UM cells. We demonstrate that Neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1, whereas HGF induces sustained activation of AKT in the presence of trametinib. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, overcomes resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts, which produce NRG1 and HGF. Analysis of metastatic liver biopsies showed that ERBB2, which is the co-receptor for NRG1, and cMET were phosphorylated in some of these clinical specimens. Our data suggest that combination of MEK inhibitors with ERBB3 and cMET targeting agents may provide novel and effective treatment strategies in metastatic UM.
Citation Format: Hanyin Cheng, Mizue Terai, Takami Sato, Andrew Aplin. Paracrine effect of NRG1 and HGF drives resistance to MEK inhibitors in metastatic uveal melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2685. doi:10.1158/1538-7445.AM2015-2685
Abstract 2686: In vivo ERK1/2 pathway reporting during acquired resistance to combined RAF/MEK inhibition
Authors: Sanchez Ileine , Aplin Andrew 
Published: August 2015

Abstract
The MEK-ERK1/2 signaling pathway is constitutively activated in BRAF V600E/K melanomas. Concurrent BRAF and MEK inhibitor treatment was recently FDA-approved for BRAF V600E melanoma; however, acquired resistance to the drug combination limits durable responses. Our lab has developed a luciferase reporter system that temporally and non-invasively quantitates ERK1/2 activity in mutant BRAF melanoma xenografts. We used this reporter system to examine the temporal kinetics of ERK1/2 activity in vivo upon treatment with combined BRAF/MEK inhibition. Using a 1205Lu reporter system, all established tumors regressed to levels that were not detectable visually. After prolonged treatment with BRAF and MEK inhibitors, only 2 out of 8 mice regrew resistant tumors. In similar experiments with A375 xenografts, only 1 out 12 tumors developed resistance. In 1205Lu tumors, re-activation of the ERK1/2 pathway was evident prior to re-growth. Additionally, cell lines generated from these resistant tumors exhibited elevated levels of ERK1/2 suggesting that resistance to BRAF + MEK inhibitors involves re-activation of ERK1/2 signaling. In comparison to parental cells, resistant cells in vitro displayed reduced levels of apoptosis, increased proliferation, and increased viability in the presence of BRAF plus MEK inhibitor. Furthermore, when removed from drugs, combination-resistant cells showed increased apoptosis and reduced proliferation and viability, suggesting that the resistant lines may be addicted to the dual therapy. RPPA analysis and whole exome sequencing to elucidate mechanisms of resistance are ongoing.
Citation Format: Ileine Sanchez, Andrew Aplin. In vivo ERK1/2 pathway reporting during acquired resistance to combined RAF/MEK inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2686. doi:10.1158/1538-7445.AM2015-2686
Abstract 2692: High allele frequency of KRAS functional mutations predicts resistance to MEK inhibitors: Evidence from cell lines and human tumor xenograft models
Authors: Reddy Anupama , Pinzon-Ortiz Maria , Derti Adnan , Korn Joshua , Ruddy David , Yang Guizhi , Green John , Gao Hui , Lehar Joseph , Caponigro Giordano , Cao Z. Alexander 
Published: August 2015

Abstract
Introduction
KRAS mutant tumors represent a high unmet need for effective therapy. Even though there is no targeted therapy for KRAS, inhibitors of downstream targets like MEK have shown efficacy in preclinical studies. However, clinical trials of MEK inhibitors in KRAS-mutant tumors have not been successful, although there have been some responders. We sought to understand resistance to MEK inhibition in KRAS-mutant tumors and to develop biomarkers for patient stratification.
Results
Using DNA and RNA sequencing data from cell lines, we found that high variant allele frequency (&gt;50%) of KRAS functional mutations (G12, G13, Q61) was associated with baseline resistance to MEK inhibitors AZD6244 and MEK162 across multiple tumor types. Low allele frequency of KRAS mutation was found to be necessary but not sufficient for sensitivity to MEK inhibitors, suggesting the existence of additional resistance mechanisms. Comparison of copy number and variant allele frequency of KRAS showed that MEK inhibitor-resistant cell lines have either amplified mutant alleles or lost WT alleles.
This prediction of high KRAS mutant allele frequency being associated with MEKi resistance was successfully validated in vivo in 19 primary colorectal tumor xenograft models treated with MEK162. High KRAS mutant allele frequency and high KRAS expression were also associated with acquired resistance to BKM120+MEK162 combination treatment in an in vivo model of HeyA8, an ovarian cell line with a KRAS G12D mutation.
This prediction was also supported by the observation in a Phase II clinical trial with MEK inhibitor refametinib + gemcitabine in pancreatic cancer [1]. Patients with disease progression had a significantly higher KRAS mutant allele frequency compared to partial responders and stable disease.
Conclusion
High allele frequency of KRAS functional mutations is associated with resistance to MEK inhibitors. Excluding patients with high KRAS mutant allele frequency has the potential to improve clinical trial outcomes and benefit patients, with the added benefit that it may not require any additional screening or novel biomarkers.
References
[1] Reiss et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 4129)
Citation Format: Anupama Reddy, Maria Pinzon-Ortiz, Adnan Derti, Joshua Korn, David Ruddy, Guizhi Yang, John Green, Hui Gao, Joseph Lehar, Giordano Caponigro, Z. Alexander Cao. High allele frequency of KRAS functional mutations predicts resistance to MEK inhibitors: Evidence from cell lines and human tumor xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2692. doi:10.1158/1538-7445.AM2015-2692
Abstract 2693: Overcoming MITF-conferred resistance through dual AURKA/MAPK-axis targeting
Authors: Pathria Gaurav , Garg Bhavuk , Garg Kanika , Borgdorff Viola , Wagner Christine , Superti-Furga Giulio , Wagner Stephan N. 
Published: August 2015

Abstract
MITF is a frequently amplified lineage-specific oncogene in human melanoma. Current drug discovery effort has, however, paradoxically ignored its criticality in melanoma cell biology and has failed to address MITF-associated intrinsic and acquired drug resistance. Here, to search the kinase targets able to circumvent the MITF-conferred intrinsic drug resistance, we used a multi-kinase inhibitor-directed chemical proteomics-based differential target affinity screen in immortalized human melanocytes carrying ectopic MITF overexpression. Through a subsequent methodical ‘gene expression-disease stage’ associations and a detailed functional interrogation in molecular-genetically diverse melanoma cellular systems, we identify a mitotic Ser/Thr kinase, Aurora Kinase A (AURKA) as a potential drug target in human melanoma that successfully overcomes MITF-engendered drug resistance phenotype. Critically, assessing the long-term efficacy of the phase II clinical trial approved highly specific AURKA-inhibitor MLN-8237, we pre-emptively witness a robust MAPK signalling-mediated immediate acquired resistance program involving MITF and Cyclin D1 induction through activity and expression changes in CREB and c-Jun respectively in both the BRAF- and NRAS-mut cells. Notably, identification of these ERK-directed acquired resistance mechanisms informed combinatorial AURKA/BRAF or AURKA/MEK targeting as an intelligent therapeutic strategy in BRAF- and NRAS-mut melanomas respectively.
Citation Format: Gaurav Pathria, Bhavuk Garg, Kanika Garg, Viola Borgdorff, Christine Wagner, Giulio Superti-Furga, Stephan N. Wagner. Overcoming MITF-conferred resistance through dual AURKA/MAPK-axis targeting. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2693. doi:10.1158/1538-7445.AM2015-2693
Abstract 2703: Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106
Authors: Alwarawrah Yazan , Hughes Philip , Safi Rachid , McDonnell Donald P. , Spector Neil L. , Haystead Timothy A. 
Published: August 2015

Abstract
Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that is overexpressed in about 20% of breast cancers and most often in the more aggressive inflammatory breast cancer (IBC). Lapatinib is one of the most potent small molecule inhibitors of HER2. Although Lapatinib has shown to be an effective targeted therapy, development of drug resistance stands as a major problem. Here we show that the anti-cancer activity of the novel fatty acid synthase inhibitor HS-106 can re-sensitize resistant cell lines to Lapatinib.
Lapatinib resistant SKBR3 and BT474 breast cancer cell lines were treated with increasing concentrations of HS-106 either alone or in combination with Lapatinib and their effects on cell proliferation were assessed using the DNA dye Hoechst 33342. The ability of HS-106 and Lapatinib drug combination to induce apoptosis were measured in Caspase 3/7 activity assay using the fluorogenic Caspase substrate (DEVD)2 R110. Their effect on apoptosis was further confirmed in Lapatinib resistant BT474 cells using flow cytometry based Annexin V assay. In addition, the effect of HS-106 on the expression levels and phosphorylation of the kinases involved in Her2 pathway including Her2, AKT and ERK were determined. The fatty acid synthase inhibitor HS-106 significantly inhibits the proliferation of Lapatinib resistant cell lines with concentrations. Interestingly, when combined with Lapatinib, the drugs synergize to dramatically affect cell growth. This anti-proliferative activity of HS-106 was found to be the result of induction of apoptosis, Caspase 3/7 activity was found to increase in a dose dependent manner following HS-106 treatment. Low concentrations of Lapatinib and HS-106, which does not induce Caspase activity when administrated separately, were found to significantly induce Caspase activity when combined together. These results were confirmed with the Annexin V assay. By examining the expression levels of HER2 pathway proteins we found a decrease in HER2 levels which was reflected on the levels of the downstream kinases AKT and ERK when treating with high concentrations of HS-106.
In a previous work, HS-106 showed a good tolerability and anti-cancer activity in the MMTV neu+ mouse model. By showing potent efficacy against Lapatinib resistant breast cancer cell lines, our data suggest that HS-106 is an excellent drug candidate to advance into translational studies for the treatment of Lapatinib resistant breast cancer.
Citation Format: Yazan Alwarawrah, Philip Hughes, Rachid Safi, Donald P. McDonnell, Neil L. Spector, Timothy A. Haystead. Overcoming Lapatinib resistance by the fatty acid synthase inhibitor HS-106. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2703. doi:10.1158/1538-7445.AM2015-2703
Abstract 2705: AKT inhibition sensitizes tumor cells to rapamycin by enhancing the repressive function of PRS40 on mTORC1/4E-BP1 axis
Authors: Mi Wenting , Ye Qing , Liu Side , She Qing-Bai 
Published: August 2015

Abstract
The mTORC1 inhibitors, rapamycin and its analogs, have been used for the treatment of a variety of cancers, but the clinical performance of these drugs has fallen short of expectations due to only modest efficacy in tumors. The underlying mechanisms of rapamycin resistance remain largely elusive. Here, we found that activated AKT signaling is associated with rapamycin resistance in breast and colon cancers by sustained phosphorylation of the translational repressor 4E-BP1. Treatment of tumor cells with rapamycin or the AKT inhibitor MK2206 shows incomplete inhibition of 4E-BP1 phosphorylation, and is functionally manifest as cap-dependent translation, cell growth and motility. However, treatment with both drugs provides profound effects in vitro and in vivo. Mechanistically, we demonstrate that the combination treatment is required to effectively inhibit PRAS40 phosphorylation on both Ser183 and Thr246 mediated by mTORC1 and AKT respectively, and with the combined treatment, dephosphorylated PRAS40 binding to the raptor/mTOR complex is enhanced, leading to dramatic repression of mTORC1-regulated 4E-BP1 phosphorylation and translation. Knockdown of PRAS40 or 4E-BP1 expression markedly reduces the dependence of tumor cells on AKT/mTORC1 signaling for translational control of cell proliferation, survival and motility. Together, these findings reveal a critical role of PRAS40 as a key integrator of mTORC1 and AKT signaling for the translational regulation of tumor cell growth and motility, and highlight PRAS40 phosphorylation as a potential surrogate marker to evaluate the therapeutic response to mTOR inhibitors.
Citation Format: Wenting Mi, Qing Ye, Side Liu, Qing-Bai She. AKT inhibition sensitizes tumor cells to rapamycin by enhancing the repressive function of PRS40 on mTORC1/4E-BP1 axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2705. doi:10.1158/1538-7445.AM2015-2705
Abstract 2709: The role of the phosphorylated RXRα on cellular proliferation and liver tumorigenesis in mice
Authors: Sakai Hiroyasu , Shirakami Yohei , Shimizu Masahito 
Published: August 2015

Abstract
We have reported that a malfunction of RXRα due to aberrant phosphorylation at serine 260 by MAPK is associated with the development of hepatocellular carcinoma (HCC) (Cancer Res 2001). The phosphorylated RXRα impairs normal receptor functions of either RXR or RAR, which are respective homodimeric or heterodimeric partner of RXRα, in a dominant-negative manner. Besides, these impaired receptor functions result in the downregulation of their target gene expression and inducing hepatocarcinogenesis by promoting cell proliferation and the inhibition of apoptosis, which suggesting that phosphorylated RXRα plays a crucial role in the development of HCC. However, these findings were revealed primarily using HCC cell lines that express the phosphorylated-RXRα (p-RXRα) proteins and it still remains unclear whether p-RXRα may impact in the process of hepatocarcinogenesis in vivo. Therefore, in order to investigate the biological functions of the p-RXRα in vivo, we generated doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress phosphomimic mutant of RXRα (T82D/S260D). We found that the T82D/S260D inducible ES cells kept undifferentiated state in differentiating media, which indicating that the phosphorylated form of RXRα plays an important role to maintain pluripotency of ES cells. On the other hand, the development of liver tumors induced by liver carcinogen diethylnitrosamine (DEN) was enhanced in the transgenic mice that overexpress T82D/S260D protein in the liver. Besides, the increased liver tumors in the transgenic mice resulted from the promotion of cell cycle progression, not the inhibition of apoptosis. Interestingly, expression of β-catenin and its target genes, cyclin D1 and c-myc, were increased in transgenic liver tumors, although the expression of retinoid-related genes, such as RARβ, p21 and p27, were not altered compared with control mice. These results suggest that a retinoid nuclear receptor, RXRα may prevent the development of DEN-induced liver tumors by regulating the canonical Wnt/β-catenin signaling pathways in mice.
Citation Format: Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu. The role of the phosphorylated RXRα on cellular proliferation and liver tumorigenesis in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2709. doi:10.1158/1538-7445.AM2015-2709
Abstract 2710: Tumorigenic activity of a novel KIF5B-RET fusion gene
Authors: Shin Jung-Young , Kim Min-Young , Son Kyoung-Hwa , Kim Jeong-Oh , Kang Jin-Hyoung 
Published: August 2015

Abstract
The KIF5B-RET gene is a novel fusion gene resulting from pericentric inversion between the kinesin family member 5B (KIF5B) and the rearranged during transfection (RET) gene, which recently isolated as an oncogene in non-small cell lung cancers. In the present study, we investigated the mechanisms associated with tumorigenic activity of KIF5B-RET fusion gene. We used a HEK-293T cell line stably expressing the KIF5B-RET fusion gene in pLOC lenti-viral vector. We investigated the tumor formation in a xenograft mouse models after subcutaneous injection and confirmed the expression of KIF5B-RET by PCR and western blot analysis. We also explored the mechanism of KIF5B-RET fusion gene in stable cell line. The KIF5B-RET stable cells showed upregulation of the cell growth, migration and colony formation. Furthermore, the KIF5B-RET stable cells induced the activation of BRAF, AKT and ERK compared with the parental cells. These results suggest that the KIF5B-RET fusion gene promotes the cell proliferation and tumorigenic activity though BRAF, AKT and ERK activation. These findings may also provide the possible that KIF5B-RET fusion gene as a ‘driver’ in some subgroups of lung cancers.
Citation Format: Jung-Young Shin, Min-Young Kim, Kyoung-Hwa Son, Jeong-Oh Kim, Jin-Hyoung Kang. Tumorigenic activity of a novel KIF5B-RET fusion gene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2710. doi:10.1158/1538-7445.AM2015-2710
Abstract 2711: Regulation of the IGF-1R signaling by angiotensin signaling pathway
Authors: Boo Hye-Jin , Jang Hyun-Ji , Jung Yujin , Min Hye-Young , Lee Ho-Young 
Published: August 2015

Abstract
Lung cancer is one of the most commonly diagnosed cancers in the world. Tobacco smoking is the most predominant risk factor for the development of lung cancer. Carcinogenic compounds in tobacco smoke are thought to be responsible for lung cancer, at least in part, by activating G-protein coupled receptor (GPCR)-mediated signaling pathways. GPCR signaling has been suggested to cross-talk with the IGF-1R signaling pathway, a key pathway for cell survival, transformation and growth. However, the mechanisms underlying the crosstalk between GPCR and IGF-1R signaling pathways remain poorly understood. Here we show that tobacco carcinogen (TC) contributes to the lung carcinogenesis by activating the angiotensin signaling and subsequent IGF-1R signaling pathways. We observed that a potent tobacco carcinogen, nitrosamine 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK, nicotine-derived nitrosamine ketone), induced transformed phenotypes, including foci formation, viability in the absence of growth factors, and anchorage-dependent and -independent colony formation, and activation of the IGF-1R in normal human bronchial epithelial cells. The NNK treatment also induced lung tumor formation in mice. Losartan, an angiotensin type-1 receptor blocker, and captopril, an angiotensin converting enzyme (ACE) inhibitor, disrupted NNK-induced IGF-1R activation and transformed phenotypes in normal human bronchial epithelial cells and reduced lung tumor formation in mice. These findings indicated that TC-induced angiotensin signaling pathway can enhance lung carcinogenesis by activating the IGF-1R signaling. Our results suggest that targeting IGF-1R by using angiotensin signaling inhibitors may be an effective strategy for the chemoprevention of lung cancer.
Citation Format: Hye-Jin Boo, Hyun-Ji Jang, Yujin Jung, Hye-Young Min, Ho-Young Lee. Regulation of the IGF-1R signaling by angiotensin signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2711. doi:10.1158/1538-7445.AM2015-2711
Abstract 2714: Effects of endosulfan on COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways
Authors: Han Eun Hee , Jun Sang Mi , Chung Young Ho 
Published: August 2015

Abstract
Endosulfan is correlated with endocrine disruption, reproductive, and immune dysfunctions. Recently, endosulfan was shown to have an effect on inflammatory pathways, but its influence on cyclooxygenase-2(COX-2) expression is unclear. This study investigated the effects of COX-2 and molecular mechanisms by endosulfan in murine macrophage RAW 264.7 cells. Endosulfan significantly induced COX-2 protein and mRNA levels, as well as COX-2 promoter-driven luciferase activity and the production of prostaglandin E2, a major COX-2 metabolite. Transfection experiments with several human COX-2 promoter constructs revealed that endosulfan activated NF-KB, C/EBP, AP-1, and CREB. Moreover, Akt and mitogen-activated protein kinases (MAPK) were significantly activated by endosulfan. Moreover, endosulfan increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2, and NOX3. These results demonstrate that endosulfan induces COX-2 expression via NADPH oxidase, ROS, and Akt/MAPK pathways. These findings provide further insight into the signal transduction pathways involved in the inflammatory effects of endosulfan.
Citation Format: Eun Hee Han, Sang Mi Jun, Young Ho Chung. Effects of endosulfan on COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2714. doi:10.1158/1538-7445.AM2015-2714