scholarly journals Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation positive lung cancer

2018 ◽  
Author(s):  
Julia K. Rotow ◽  
Philippe Gui ◽  
Wei Wu ◽  
Victoria M. Raymond ◽  
Richard B. Lanman ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Preclinical Model ◽  
Sequencing Analysis ◽  
Advanced Stage ◽  
Acquired Drug Resistance ◽  
Therapy Strategy ◽  
Pathway Gene ◽  
Tki Treatment

AbstractPURPOSEWhile patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.METHODSTargeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.RESULTSProminent co-occurring RAS-MAPK pathway gene alterations (e.g. in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared to EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib.CONCLUSIONOur study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

IGFBP-7 to confer resistance to the epidermal growth factor receptor tyrosine kinase inhibitor.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20572-e20572
Author(s):  
Shang-Gin Wu ◽  
Tzu-Hua Chang ◽  
Yih-Leong Chang ◽  
Meng-Feng Tsai ◽  
Chong-Jen Yu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
First Line ◽  
Free Survival ◽  
Acquired Drug Resistance ◽  
Tki Resistance ◽  
Tki Treatment ◽  
Gefitinib Resistance ◽  
Egfr Tki

e20572 Background: Lung cancer is a leading cause of cancer death worldwide. The EGFR mutation-positive patients of lung adenocarcinoma had dramatic response to EGFR tyrosine kinase inhibitors (TKIs). However, acquired drug resistance developed invariably after one year treatment course of EGFR TKI. IGFBP-7, a secreted 31 kDa protein, exhibits low affinity for IGF but binds strongly to insulin. No previous studies had been mentioned the correlation between the protein and acquired EGFR TKI resistance. Methods: cDNA microarray was used to screen differentially expressed genes between EGFR TKI-sensitive (PC9 and HCC827) and acquired EGFR TKIs-resistance cell lines (PC9/gef and HCC827/gef). The expression levels of the screened genes were validated by RT -PCR and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of IGFBP-7 on gefitinib resistance in vitro. In addition, clinical specimens were collected to validate the imact of IGFBP-7 on the efficacy of EGFR TKI treatment . Results: IGFBP-7 is over-expressed in gefitinib-resistant cells. The IGFBP-7 mRNA expression in the malignant pleural effusion of patients with acquired resistance to EGFR TKI was significant higher than that in the treatment-naïve patients. Knockdown IGFBP-7 reverses gefitinib resistance in PC9/gef cells. Knockdown IGFBP-7 could increase gefetinib induced-apoptosis through the regulation of BIM. IGFBP-7 affected the mechanism of EGFR TKI resistance resulted from inhibition of IGF-IR.. In clinical practice, low IGFBP-7 serum level is associated with longer progression free survival (PFS) of EGFR TKI as the first line treatment. Furthermore, lower IGFBP-7 level of resected tumor predicts a longer 5-year tumor relapse-free survival. Positive IGFBP-7 immunoihistochemical stain could predict a shorter PFS of the first-line EGFR TKI treatment. Conclusions: IGFBP-7 confers resistance to the EGFR TKI and may be a target for future treatment investigation.

scholarly journals Immunomodulatory activity of Ganoderma lucidum immunomodulatory protein via PI3K/Akt and MAPK signaling pathways in macrophage RAW264.7 cells

2018 ◽  
Author(s):  
Xuanwei Zhou ◽  
Qizhang Li ◽  
Yuzhou Chang ◽  
Liu-Ding-Ji Li ◽  
Xiaoyu Du ◽  
...  
Keyword(s):  
Ganoderma Lucidum ◽  
Kinase Inhibitor ◽  
Mapk Signaling ◽  
Raw264.7 Cells ◽  
In Vitro Assays ◽  
Immunomodulatory Activity ◽  
Inos Mrna ◽  
Sequencing Analysis ◽  
Mrna Levels ◽  
Immunomodulatory Protein

Ganoderma lucidum, a traditional edible and medicinal fungus, holds an important status in health care systems in China and other Asian countries. Fungal immunomodulatory protein (FIP), one of the active ingredients isolated from G. lucidum, is a class of naturally occurring proteins and possesses potential biological functions. This study was conducted to explore the molecular mechanism of its immunomodulatory potency in immune responses of macrophages. In vitro assays of biological activity indicated that rFIP-glu significantly activated macrophage RAW264.7 cells, and possessed the ability of pro- and anti-inflammation the cells. RNA sequencing analysis showed that macrophage activation involved Toll-like receptors and mitogen-activated protein kinases pathways. Furthermore, qRT-PCR indicated that phosphoinositide 3 kinase inhibitor LY294002 blocked the mRNA levels of MCP-1, MEK1/2 inhibitor U0126 reduced the mRNA levels of TNF-α and MCP-1, and JNK inhibitor SP600125 prevented the up-regulation of iNOS mRNA in the rFIP-glu-induced cells. FIP-glu mediated these inflammatory effects not through a general pathway, instead through a different pathway for different inflammatory mediator. These data indicate the possibility that rFIP-glu has an important immune-regulation function and thus has potential therapeutic uses.

scholarly journals Ras/MAPK modifier loci revealed by eQTL in C. elegans

2017 ◽  
Author(s):  
Mark G. Sterken ◽  
Linda van Bemmelen van der Plaat ◽  
Joost A. G. Riksen ◽  
Miriam Rodriguez ◽  
Tobias Schmid ◽  
...  
Keyword(s):  
Genetic Background ◽  
Gene Expression Regulation ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
C Elegans ◽  
Oncogenic Ras ◽  
Pathway Gene ◽  
Evolutionarily Conserved ◽  
Transgenic Lines ◽  
Almost All

ABSTRACTThe oncogenic Ras/MAPK pathway is evolutionarily conserved across metazoans. Yet, almost all our knowledge on this pathway comes from studies using single genetic backgrounds, whereas mutational effects can be highly background dependent. Therefore, we lack insight in the interplay between genetic backgrounds and the Ras/MAPK-signaling pathway. Here, we used a Caenorhabditis elegans RIL population containing a gain-of-function mutation in the Ras/MAPK pathway gene let-60 and measured how gene expression regulation is affected by this mutation. We mapped eQTL and found that the majority (~73%) of the 1516 detected cis-eQTL were not specific for the let-60 mutation, whereas most (~76%) of the 898 detected trans-eQTL were associated with the let-60 mutation. We detected 6 eQTL trans-bands specific for the interaction between the genetic background and the mutation, one of which co-localized with the polymorphic Ras/MAPK modifier amx-2. Comparison between transgenic lines expressing allelic variants of amx-2 showed the involvement of amx-2 in 79% of the trans-eQTL for genes mapping to this trans-band. Together, our results have revealed loci hidden loci affecting Ras/MAPK signaling using sensitized backgrounds in C. elegans. These loci harbor putative polymorphic modifier genes that would not have been detected using mutant screens in single genetic backgrounds.

scholarly journals PTEN Status Alters the Molecular Route to Resistance to BRAF Inhibitor in Melanoma

2019 ◽  
pp. 1-3
Author(s):  
Qiang Zuo ◽  
Yanlin Yu
Keyword(s):  
Mapk Pathway ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Acquired Drug Resistance ◽  
Survival Pathway ◽  
Clinical Benefits ◽  
Dual Inhibitors ◽  
Melanoma Patients

Although targeted treatment by BRAF inhibitors (BRAFi) achieved a remarkable clinical response for patients with BRAF mutation, the strength of efficacy is short and limited by acquired drug resistance [1]. Recent studies identified many mechanisms of acquired resistance to BRAFi, such as mutations in NRAS or MEK1 and overexpression of COT, EGFR, PDGFRβ, IGF1R or MET, lead the reactivation of MAPK pathway and drive the cell proliferation, suggesting that co-targeting this hyperactivated survival pathway by combination inhibitors might gain the maximum clinical benefits for melanoma patients [2]. Based on these findings, FDA approved the combination of dabrafenib (BRAFi) with trametinib (MEK inhibitor) or vemurafenib (BRAFi) with cobimetinib (MEK inhibitor) to inhibit the MAPK signaling pathway in 2014 and 2015 more effectively. Indeed, the dual inhibitors of MEK and mutant BRAF kinases have shown a higher overall survival rate and exciting results in initial tumor response in clinical.

scholarly journals Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Oliver A. Kent ◽  
Manipa Saha ◽  
Etienne Coyaud ◽  
Helen E. Burston ◽  
Napoleon Law ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Mapk Signaling ◽  
Epigenetic Reprogramming ◽  
Gene Promoters ◽  
Pathway Gene ◽  
Element Binding Protein ◽  
Molecular Etiology ◽  
The Common ◽  
Spectrum Disorders ◽  
Responsive Element

Abstract RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.

Tyrosine kinase inhibitor (TKI) treatment outcome of stage IV-C thyroid differentiated cancer (analyzed by lesion evaluation)

2018 ◽  
Author(s):  
Hiroyuki Iwasaki ◽  
Haruhiko Yamazaki ◽  
Nobuyasu Suganuma ◽  
Yuko Sugawara ◽  
Naoki Gotoh ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Stage Iv ◽  
Tki Treatment

Germline EGFR variants are over-represented in adolescents and young adults (AYA) with adrenocortical carcinoma

2020 ◽  
Author(s):  
Sara Akhavanfard ◽  
Lamis Yehia ◽  
Roshan Padmanabhan ◽  
Jordan P Reynolds ◽  
Ying Ni ◽  
...  
Keyword(s):  
Young Adults ◽  
Adrenocortical Carcinoma ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Adolescents And Young Adults ◽  
Control Group ◽  
Precision Oncology ◽  
Sequencing Data ◽  
Germline Variants ◽  
Mutant Cells

Abstract Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and 1.5-fold overrepresentation in females. In children, ACC is associated with inherited cancer syndromes with 50–80% of childhood-ACC associated with TP53 germline variants. ACC in adolescents and young adults (AYA) is rarely due to germline TP53, IGF2, PRKAR1A and MEN1 variants. We analyzed exome sequencing data from 21 children (<15y), 32 AYA (15-39y), and 60 adults (>39y) with ACC, and retained all pathogenic, likely pathogenic, and highly prioritized variants of uncertain significance. We engineered a stable lentiviral-mutant ACC cell line, harboring an EGFR variant (p.Asp1080Asn) from a 21-year-old female without germline-TP53-variant and with aggressive ACC. We found that 4.8% of the children (P = 0.004) and 6.2% of AYA (P < 0.0001), all-female participants, harbored germline EGFR variants, compared to only 0.3% of the control group. Expanding our analysis to the RTK-RAS-MAPK pathway, we found that the RTK genes have the highest number of highly prioritized germline variants in these individuals amongst all three arms of this pathway. We showed EGFR mutant cells migrate faster and are characterized by a stem-like phenotype compared to wild type cells. While EGFR inhibitors did not affect the stemness of mutant cells, Sunitinib, a multireceptor tyrosine kinase inhibitor, significantly reduced their stem-like behavior. Our data suggest that EGFR could be a novel underlying germline predisposition factor for ACC, especially in the Childhood-AYA (C-AYA) population. Further clinical validation can improve precision oncology management of this disease, which is known to have limited therapeutic options.

scholarly journals Brassinin Inhibits Proliferation in Human Liver Cancer Cells via Mitochondrial Dysfunction

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 332
Author(s):  
Taeyeon Hong ◽  
Jiyeon Ham ◽  
Jisoo Song ◽  
Gwonhwa Song ◽  
Whasun Lim
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Nuclear Antigen ◽  
Cruciferous Vegetable ◽  
Antiproliferative Effects ◽  
Hep3b Cells ◽  
Human Liver Cancer Cells

Brassinin is a phytochemical derived from Chinese cabbage, a cruciferous vegetable. Brassinin has shown anticancer effects on prostate and colon cancer cells, among others. However, its mechanisms and effects on hepatocellular carcinoma (HCC) have not been elucidated yet. Our results confirmed that brassinin exerted antiproliferative effects by reducing proliferating cell nuclear antigen (PCNA) activity, a proliferation indicator and inducing cell cycle arrest in human HCC (Huh7 and Hep3B) cells. Brassinin also increased mitochondrial Ca2+ levels and depolarized the mitochondrial membrane in both Huh7 and Hep3B cells. Moreover, brassinin generated high amounts of reactive oxygen species (ROS) in both cell lines. The ROS scavenger N-acetyl-L-cysteine (NAC) inhibited this brassinin-induced ROS production. Brassinin also regulated the AKT and mitogen-activated protein kinases (MAPK) signaling pathways in Huh7 and Hep3B cells. Furthermore, co-administering brassinin and pharmacological inhibitors for JNK, ERK1/2 and P38 decreased cell proliferation in both HCC cell lines more than the pharmacological inhibitors alone. Collectively, our results demonstrated that brassinin exerts antiproliferative effects via mitochondrial dysfunction and MAPK pathway regulation on HCC cells.

scholarly journals The In Vitro Effect of Steroid Hormones, Arachidonic Acid, and Kinases Inhibitors on Aquaporin 1, 2, 5, and 7 Gene Expression in the Porcine Uterine Luminal Epithelial Cells during the Estrous Cycle

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 832
Author(s):  
Damian Tanski ◽  
Agnieszka Skowronska ◽  
Malgorzata Tanska ◽  
Ewa Lepiarczyk ◽  
Mariusz T. Skowronski
Keyword(s):  
Arachidonic Acid ◽  
Epithelial Cells ◽  
Steroid Hormones ◽  
Estrous Cycle ◽  
Kinase Inhibitor ◽  
Mapk Signaling ◽  
Mapk Kinase ◽  
Vitro Effect ◽  
Luminal Epithelial Cells

Aquaporins (AQPs) are integral membrane proteins, which play an important role in water homeostasis in the uterus. According to the literature, the expression of aquaporins in reproductive structures depends on the local hormonal milieu. The current study investigated the effect of selected PKA kinase inhibitor H89 and MAPK kinase inhibitor PD98059, on the expression of AQP1, 2, 5, and 7, and steroid hormones (E2), progesterone (P4), and arachidonic acid (AA) in the porcine endometrium on days 18–20 and 2–4 of the estrous cycle (the follicular phase where estrogen and follicle-stimulating hormone (FSH) are secreted increasingly in preparation for estrus and the luteal phase where the ovarian follicles begin the process of luteinization with the formation of the corpus luteum and progesterone secretion, respectively). The luminal epithelial cells were incubated in vitro in the presence of the aforementioned factors. The expression of mRNA was determined by the quantitative real-time PCR technique. In general, in Experiment 1, steroid hormones significantly increased expression of AQP1, 2, and 5 while arachidonic acid increased expression of AQP2 and AQP7. On the other hand, MAPK kinase inhibitor significantly decreased the expression of AQP1 and 5. In Experiment 2, E2, P4, or AA combined with kinase inhibitors differentially affected on AQPs expression. E2 in combination with PKA inhibitor significantly decreased expression of AQP1 but E2 or P4 combined with this inhibitor increased the expression of AQP5 and 7. On the contrary, E2 with PD98059 significantly increased AQP5 and AQP7 expression. Progesterone in combination with MAPK kinase inhibitor significantly downregulated the expression of AQP5 and upregulated AQP7. Arachidonic acid mixed with H89 or PD98059 caused a decrease in the expression of AQP5 and an increase of AQP7. The obtained results indicate that estradiol, progesterone, and arachidonic acid through PKA and MAPK signaling pathways regulate the expression of AQP1 and AQP5 in the porcine luminal epithelial cells in the periovulatory period.

scholarly journals Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

2021 ◽  
Author(s):  
Kuan-Wei Su ◽  
Da-Liang Ou ◽  
Yu-Hsuan Fu ◽  
Hwei-Fang Tien ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Ribosome Biogenesis ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Leukocyte Activation ◽  
Mouse Xenograft Model ◽  
Acute Myeloid

AbstractCabozantinib is an orally available, multi-target tyrosine kinase inhibitor approved for the treatment of several solid tumours and known to inhibit KIT tyrosine kinase. In acute myeloid leukaemia (AML), aberrant KIT tyrosine kinase often coexists with t(8;21) to drive leukaemogenesis. Here we evaluated the potential therapeutic effect of cabozantinib on a selected AML subtype characterised by t(8;21) coupled with KIT mutation. Cabozantinib exerted substantial cytotoxicity in Kasumi-1 cells with an IC50 of 88.06 ± 4.32 nM, which was well within clinically achievable plasma levels. The suppression of KIT phosphorylation and its downstream signals, including AKT/mTOR, STAT3, and ERK1/2, was elicited by cabozantinib treatment and associated with subsequent alterations of cell cycle- and apoptosis-related molecules. Cabozantinib also disrupted the synthesis of an AML1-ETO fusion protein in a dose- and time-dependent manner. In a mouse xenograft model, cabozantinib suppressed tumourigenesis at 10 mg/kg and significantly prolonged survival of the mice. Further RNA-sequencing analysis revealed that mTOR-mediated signalling pathways were substantially inactivated by cabozantinib treatment, causing the downregulation of ribosome biogenesis and glycolysis, along with myeloid leukocyte activation. We suggest that cabozantinib may be effective in the treatment of AML with t(8;21) and KIT mutation. Relevant clinical trials are warranted.

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