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1دورية أكاديمية
المؤلفون: Yu Gao, Eva-Maria Packeiser, Sophia Wendt, Anett Sekora, Jessika-Maximiliane V. Cavalleri, Barbara Pratscher, Moosheer Alammar, Maja Hühns, Bertram Brenig, Christian Junghanss, Ingo Nolte, Hugo Murua Escobar
المصدر: Genes, Vol 15, Iss 2, p 202 (2024)
مصطلحات موضوعية: equine malignant melanoma, canine malignant melanoma, Pan-RAF inhibitor, LY3009120, DNA sequencing, genetic evaluation, Genetics, QH426-470
الوصف: Malignant melanomas (MMs) are the abnormal proliferation of melanocytes and are one of the lethal skin cancers in humans, equines, and canines. Accordingly, MMs in companion animals can serve as naturally occurring animal models, completing conventional cancer models. The common constitutive activation of the MAPK and PI3K pathways in MMs has been described in all three species. Targeting the related pathways is considered a potential option in comparative oncologic approaches. Herein, we present a cross-species comparative analysis exposing a set of ten melanoma cell lines (one human, three equine, and six canine) derived from primary tumors or metastasis to a pan-RAF and RAF dimer inhibitor (LY3009120). Cellular response (proliferation, biomass, metabolism, early and late apoptosis/necrosis, and morphology) and the presence of pathogenic single-nucleotide variants (SNVs) within the mutational hotspot genes BRAF exon 11 and 15, NRAS exon 2 and 3, KRAS exon 2, and KIT exon 11 were analyzed. This study showed that equine malignant melanoma (EMM) cells (MelDuWi) harbor the KRAS p.Q61H mutation, while canine malignant melanoma (CMM) cells (cRGO1 and cRGO1.2) carry NRAS p.G13R. Except for EMM metastasis cells eRGO6 (wild type of the above-mentioned hotspot genes), all melanoma cell lines exhibited a decrease in dose dependence after 48 and 72 h of exposure to LY3009120, independent of the mutation hotspot landscape. Furthermore, LY3009120 caused significant early apoptosis and late apoptosis/necrosis in all melanoma cell lines except for eRGO6. The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the NRAS p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology.
وصف الملف: electronic resource
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2دورية أكاديمية
المؤلفون: Annika Ladwig, Shailendra Gupta, Peter Ehlers, Anett Sekora, Moosheer Alammar, Dirk Koczan, Olaf Wolkenhauer, Christian Junghanss, Peter Langer, Hugo Murua Escobar
المصدر: Molecules, Vol 28, Iss 24, p 8120 (2023)
مصطلحات موضوعية: anti-proliferative, apoptosis, lymphoma, B-ALL, thiazolopyridine, target-screening, Organic chemistry, QD241-441
الوصف: Thiazolopyridines are a highly relevant class of small molecules, which have previously shown a wide range of biological activities. Besides their anti-tubercular, anti-microbial and anti-viral activities, they also show anti-cancerogenic properties, and play a role as inhibitors of cancer-related proteins. Herein, the biological effects of the thiazolopyridine AV25R, a novel small molecule with unknown biological effects, were characterized. Screening of a set of lymphoma (SUP-T1, SU-DHL-4) and B- acute leukemia cell lines (RS4;11, SEM) revealed highly selective effects of AV25R. The selective anti-proliferative and metabolism-modulating effects were observed in vitro for the B-ALL cell line RS4;11. Further, we were able to detect severe morphological changes and the induction of apoptosis. Gene expression analysis identified a large number of differentially expressed genes after AV25R exposure and significant differentially regulated cancer-related signaling pathways, such as VEGFA-VEGFR2 signaling and the EGF/EGFR pathway. Structure-based pharmacophore screening approaches using in silico modeling identified potential biological AV25R targets. Our results indicate that AV25R binds with several proteins known to regulate cell proliferation and tumor progression, such as FECH, MAP11, EGFR, TGFBR1 and MDM2. The molecular docking analyses indicates that AV25R has a higher binding affinity compared to many of the experimentally validated small molecule inhibitors of these targets. Thus, here we present in vitro and in silico analyses which characterize, for the first time, the molecular acting mechanism of AV25R, including cellular and molecular biologic effects. Additionally, this predicted the target binding of the molecule, revealing a high affinity to cancer-related proteins and, thus, classified AVR25 for targeted intervention approaches.
وصف الملف: electronic resource
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3دورية أكاديمية
المؤلفون: Anna Richter, Sandra Lange, Clemens Holz, Luisa Brock, Thomas Freitag, Anett Sekora, Gudrun Knuebel, Saskia Krohn, Rico Schwarz, Burkhard Hinz, Hugo Murua Escobar, Christian Junghanss
المصدر: Cell Death Discovery, Vol 8, Iss 1, Pp 1-11 (2022)
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
الوصف: Abstract Dysregulation of the intrinsic BCL-2 pathway-mediated apoptosis cascade is a common feature of hematological malignancies including acute B-lymphoblastic leukemia (B-ALL). The KMT2A-rearranged high-risk cytogenetic subtype is characterized by high expression of antiapoptotic protein BCL-2, likely due to the direct activating binding of KMT2A fusion proteins to the BCL2 gene. The BCL-2 inhibitor venetoclax (VEN) has proven great clinical value in other blood cancers, however, data on B-ALL is sparse and past studies have not so far described the effects of VEN on gene and protein expression profiles. Using cell lines and patient-derived in vivo xenograft models, we show BCL-2 pathway-mediated apoptosis induction and decelerated tumor cell counts in KMT2A-rearranged B-ALL but not in other cytogenetic subtypes. VEN treatment of cell line- and patient-derived xenografts reduced blast frequencies in blood, bone marrow, and spleen, and tumor cell doubling times were increased. Growth rates are further correlated with VEN concentrations in blood. In vitro incubation with VEN resulted in BCL-2 dephosphorylation and targeted panel RNA sequencing revealed reduced gene expression of antiapoptotic pathway members BCL2, MCL1, and BCL2L1 (BCL-XL). Reinforced translocation of BAX proteins towards mitochondria induced caspase activation and cell death commitment. Prolonged VEN application led to upregulation of antiapoptotic proteins BCL-2, MCL-1, and BCL-XL. Interestingly, the extrinsic apoptosis pathway was strongly modulated in SEM cells in response to VEN. Gene expression of members of the tumor necrosis factor signaling cascade was increased, resulting in canonical NF-kB signaling. This possibly suggests a previously undescribed mechanism of BCL-2-independent and NF-kB-mediated upregulation of MCL-1 and BCL-XL. In summary, we herein prove that VEN is a potent option to suppress tumor cells in KMT2A-rearranged B-ALL in vitro and in vivo. Possible evasion mechanisms, however, must be considered in subsequent studies.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2058-7716Test
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4دورية أكاديمية
المؤلفون: Clemens Holz, Sandra Lange, Anett Sekora, Gudrun Knuebel, Saskia Krohn, Hugo Murua Escobar, Christian Junghanss, Anna Richter
المصدر: International Journal of Molecular Sciences, Vol 24, Iss 2, p 1359 (2023)
مصطلحات موضوعية: acute lymphoblastic leukemia, B-ALL, BCL-2, venetoclax, apoptosis, PI3K/AKT inhibition, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with KMT2A rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene BBC3 as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.
وصف الملف: electronic resource
العلاقة: https://www.mdpi.com/1422-0067/24/2/1359Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test
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5دورية أكاديمية
المؤلفون: Wen Liu, Sina Sender, Weibo Kong, Julia Beck, Anett Sekora, Kirsten Bornemann-Kolatzki, Ekkehart Schuetz, Christian Junghanss, Bertram Brenig, Ingo Nolte, Hugo Murua Escobar
المصدر: Cancer Cell International, Vol 20, Iss 1, Pp 1-11 (2020)
مصطلحات موضوعية: Prostate cancer, Canine, Cell line, Far-red, Near infra-red, Imaging, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
الوصف: Abstract Background Canine prostate cancer represents a unique model for human prostate cancer. In vitro systems offer various possibilities but Xenograft in vivo imaging allows studying complex tasks as tumor progression and drug intervention longitudinal. Herein, we established three canine prostate carcinoma cell lines stably expressing fluorescent proteins allowing deep tissue in vivo imaging. Methods Three canine prostate carcinoma (cPC) cell lines were stably transfected with fluorescent proteins in red, far-red and near infra-red spectrum, followed by G418 selection. Fluorescent protein expression was demonstrated by microscopy, flow cytometry and a NightOWL LB 983 in vivo imaging system. Cellular and molecular characteristics of the generated cell lines were compared to the parental cell line CT1258. Cell proliferation, metabolic activity and sphere formation capacity were analyzed. Stem cell marker expression was examined by qPCR and genomic copy number variation by genomic DNA whole genome sequencing. Results Three stably fluorescent protein transfected cPC cell lines were established and characterized. Compared to the parental cell line, no significant difference in cell proliferation and metabolic activity were detected. Genomic copy number variation analyses and stem cell marker gene expression revealed in general no significant changes. However, the generated cell line CT1258-mKate2C showed uniquely no distal CFA16 deletion and an elevated metabolic activity. The introduced fluorescencent proteins allowed highly sensitive detection in an in vivo imaging system starting at cell numbers of 0.156 × 106. Furthermore, we demonstrated a similar sphere formation capacity in the fluorescent cell lines. Interestingly, the clone selected CT1258-mKate2C, showed increased sphere formation ability. Discussion Starting from a well characterized cPC cell line three novel fluorescent cell lines were established showing high cellular and molecular similarity to the parental cell line. The introduction of the fluorescent proteins did not alter the established cell lines significantly. The red fluorescence allows deep tissue imaging, which conventional GFP labeling is not able to realize. Conclusion As no significant differences were detected between the established cell lines and the very well characterized parental CT1258 the new fluorescent cell lines allow deep tissue in vivo imaging for perspective in vivo evaluation of novel therapeutic regimens.
وصف الملف: electronic resource
العلاقة: http://link.springer.com/article/10.1186/s12935-020-01211-0Test; https://doaj.org/toc/1475-2867Test
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6دورية أكاديمية
المؤلفون: Anna Richter, Sina Sender, Annemarie Lenz, Rico Schwarz, Burkhard Hinz, Gudrun Knuebel, Anett Sekora, Hugo Murua Escobar, Christian Junghanss, Catrin Roolf
المصدر: BMC Cancer, Vol 20, Iss 1, Pp 1-10 (2020)
مصطلحات موضوعية: B-ALL, Apoptosis, CK2, CX-4945, BCL6, BACH2, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract Background Casein kinase II (CK2) is involved in multiple tumor-relevant signaling pathways affecting proliferation and apoptosis. CK2 is frequently upregulated in acute B-lymphoblastic leukemia (B-ALL) and can be targeted by the ATP-competitive CK2 inhibitor CX-4945. While reduced proliferation of tumor entities including B-ALL after CX-4945 incubation has been shown in vitro and in vivo, the detailed way of action is unknown. Here, we investigated the influence on the PI3K/AKT and apoptosis cascades in vivo and in vitro for further clarification. Methods A B-ALL xenograft model in NSG mice was used to perform in vivo longitudinal bioluminescence imaging during six day CX-4945 treatment. CX-4945 serum levels were determined at various time points. Flow cytometry of bone marrow and spleen cells was performed to analyze CX-4945-induced effects on tumor cell proliferation and distribution in B-ALL engrafted mice. ALL cells were enriched and characterized by targeted RNA sequencing. In vitro, B-ALL cell lines SEM, RS4;11 and NALM-6 were incubated with CX-4945 and gene expression of apoptosis regulators BCL6 and BACH2 was determined. Results In B-ALL-engrafted mice, overall tumor cell proliferation and distribution was not significantly influenced by CK2 inhibition. CX-4945 was detectable in serum during therapy and serum levels declined rapidly after cessation of CX-4945. While overall proliferation was not affected, early bone marrow and spleen blast frequencies seemed reduced after CK2 inhibition. Gene expression analyses revealed reduced expression of anti-apoptotic oncogene BCL6 in bone marrow blasts of CX-4945-treated animals. Further, BCL6 protein expression decreased in B-ALL cell lines exposed to CX-4945 in vitro. Surprisingly, levels of BCL6 opponent and tumor suppressor BACH2 also declined after prolonged incubation. Simultaneously, increased phosphorylation of direct CK2 target and tumor initiator AKT was detected at respective time points, even in initially pAKT-negative cell line NALM-6. Conclusions The CK2 inhibitor CX-4945 has limited clinical effects in an in vivo B-ALL xenograft model when applied as a single drug over a six day period. However, gene expression in B-ALL cells was altered and suggested effects on apoptosis via downregulation of BCL6. Unexpectedly, the BCL6 opponent BACH2 was also reduced. Interactions and regulation loops have to be further evaluated.
وصف الملف: electronic resource
العلاقة: http://link.springer.com/article/10.1186/s12885-020-6650-9Test; https://doaj.org/toc/1471-2407Test
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7دورية أكاديمية
المؤلفون: Yixuan Ma, Benjamin Schulz, Nares Trakooljul, Moosheer Al Ammar, Anett Sekora, Sina Sender, Frieder Hadlich, Dietmar Zechner, Frank Ulrich Weiss, Markus M. Lerch, Robert Jaster, Christian Junghanss, Hugo Murua Escobar
المصدر: Cancers, Vol 14, Iss 18, p 4467 (2022)
مصطلحات موضوعية: pancreatic ductal adenocarcinoma, KRAS, kinase inhibitors, gene expression, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used in PDAC patients. We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. Whole transcriptomic analysis of combined inhibition and control groups were comparatively analyzed to explore the corresponding mechanisms of inhibitor combination. Both KRAS inhibitors and corresponding combinations exhibited cytotoxicity against specific PDAC cell lines. BI-3406 enhance the efficacy of trametinib and buparlisib in BXPC-3, ASPC-1 and MIA PACA-2, but not in CAPAN-1, while sotorasib enhances the efficacy of trametinib and buparlisib only in MIA PACA-2. The whole transcriptomic analysis demonstrates that the two triple-inhibitor combinations exert antitumor effects by affecting related cell functions, such as affecting the immune system, cell adhesion, cell migration, and cytokine binding. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations.
وصف الملف: electronic resource
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8دورية أكاديمية
المؤلفون: Sina Sender, Ahmad Wael Sultan, Daniel Palmer, Dirk Koczan, Anett Sekora, Julia Beck, Ekkehard Schuetz, Leila Taher, Bertram Brenig, Georg Fuellen, Christian Junghanss, Hugo Murua Escobar
المصدر: Cancers, Vol 14, Iss 19, p 4691 (2022)
مصطلحات موضوعية: BET, I-BET151, AZD5153, entospletinib, SYK, gene expression, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Background: Both bromodomain and extra-terminal domain (BET) proteins and spleen tyrosine kinase (SYK) represent promising targets in diffuse large B-cell (DLBCL) and Burkitt’s lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. Methods: The effect of the single agents on cell proliferation and metabolic activity was evaluated in two DLBCL and two BL cell lines. Proliferation, metabolic activity, apoptosis, cell cycle and morphology were further investigated after a combined treatment of AZD or I-BET and Ento. RNAseq profiling of combined AZD+Ento treatment was performed in SU-DHL-4 cells. Results: Both BET inhibitors reduced cell proliferation and metabolic activity in a dose- and time-dependent manner. Combined BET and SYK inhibition enhanced the anti-proliferative effect and induced a G0/G1 cell cycle arrest. SU-DHL-4 demonstrated a pronounced modulation of gene expression by AZD, which was markedly increased by additional SYK inhibition. Functional enrichment analyses identified combination-specific GO terms related to DNA replication and cell division. Genes such as ADGRA2, MYB, TNFRSF11A, S100A10, PLEKHH3, DHRS2 and FOXP1-AS1 were identified as possible key regulators. Conclusion: Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature.
وصف الملف: electronic resource
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9دورية أكاديمية
المؤلفون: Anna Richter, Catrin Roolf, Mohamed Hamed, Yvonne Saara Gladbach, Sina Sender, Christoph Konkolefski, Gudrun Knübel, Anett Sekora, Georg Fuellen, Brigitte Vollmar, Hugo Murua Escobar, Christian Junghanss
المصدر: BMC Cancer, Vol 19, Iss 1, Pp 1-11 (2019)
مصطلحات موضوعية: Leukemia, CK2 inhibition, Hypomethylation, In vivo imaging, Methylome analysis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract Background The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3K/AKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways. Methods Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3K/AKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice. Results CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(4;11) translocation were heterogeneous. Conclusions We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL.
وصف الملف: electronic resource
العلاقة: http://link.springer.com/article/10.1186/s12885-019-5411-0Test; https://doaj.org/toc/1471-2407Test
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10دورية أكاديمية
المؤلفون: Yixuan Ma, Sina Sender, Anett Sekora, Weibo Kong, Peter Bauer, Najim Ameziane, Ruslan Al-Ali, Susann Krake, Mandy Radefeldt, Frank Ulrich Weiss, Markus M. Lerch, Alisha Parveen, Dietmar Zechner, Christian Junghanss, Hugo Murua Escobar
المصدر: International Journal of Molecular Sciences, Vol 23, Iss 8, p 4295 (2022)
مصطلحات موضوعية: PI3K/AKT pathway, pancreatic ductal adenocarcinoma, KRAS, TP53, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors.
وصف الملف: electronic resource
العلاقة: https://www.mdpi.com/1422-0067/23/8/4295Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test
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