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Suppression of mutant Kirsten-RAS (KRASG12D)-driven pancreatic carcinogenesis by dual-specificity MAP kinase phosphatases 5 and 6

Oncogene

2022 Apr 13

Kidger, AM;Saville, MK;Rushworth, LK;Davidson, J;Stellzig, J;Ono, M;Kuebelsbeck, LA;Janssen, KP;Holzmann, B;Morton, JP;Sansom, OJ;Caunt, CJ;Keyse, SM;
PMID: 35418690 | DOI: 10.1038/s41388-022-02302-0

The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRASG12D-driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRASG12D-driven pancreatic hyperplasia. This is accompanied by increased pancreatic acinar to ductal metaplasia (ADM) and the development of pre-neoplastic pancreatic intraepithelial neoplasia (PanINs). In contrast, by 100-days, pancreatic hyperplasia is reversed with significant atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. On further ageing, Dusp6-/- mice display accelerated development of metastatic pancreatic ductal adenocarcinoma (PDAC), while in Dusp5-/- animals, although PDAC development is increased this process is attenuated by atrophy of pancreatic acinar tissue and severe weight loss in some animals before cancer could progress. Our data suggest that despite a common target in the ERK MAP kinase, DUSP5 and DUSP6 play partially non-redundant roles in suppressing oncogenic KRASG12D signalling, thus retarding both tumour initiation and progression. Our data suggest that loss of either DUSP5 or DUSP6, as observed in certain human tumours, including the pancreas, could promote carcinogenesis.
Oncofetal Long Noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2

Hepatology

Wang F, Yuan JH, Wang SB, Yang F, Yuan SX, Ye C, Yang N, Zhou WP, Li WL, Li W, Sun SH
PMID: 10.1002/hep.27239

Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein, we examined the expression profiles of long non-coding RNAs (lncRNAs) found in fetal and adult liver in mice. Many fetal hepatic lncRNAs were identified; one of these, lncRNA-mPvt1, is an oncofetal RNA that was found to promote cell proliferation, cell cycling and the expression of stem cell-like properties of murine cells. Interestingly, we found that human lncRNA-hPVT1 was up-regulated in HCC tissues and that patients with higher lncRNA-hPVT1 expression had poor clinical prognosis. The protumorigenic effects of lncRNA-hPVT1 on cell proliferation, cell cycling and stem cell-like properties of HCC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Moreover, mRNA expression profile data showed that lncRNA-hPVT1 up-regulated a series of cell cycle genes in SMMC-7721 cells. By RNA pulldown and mass spectrum experiments, we identified NOP2 as an RNA-binding protein that binds to lncRNA-hPVT1. We confirmed that lncRNA-hPVT1 up-regulated NOP2 by enhancing the stability of NOP2 proteins and that lncRNA-hPVT1 function depends on the presence of NOP2. Conclusion: Our study demonstrates that the expression of many lncRNAs is up-regulated in early liver development and that the fetal liver can be used to search for new diagnostic markers for HCC. LncRNA-hPVT1 promotes cell proliferation, cell cycling and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects in the treatment of HCC. (Hepatology 2014;)
Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

Nature cancer

2022 Jul 01

Wilding, B;Scharn, D;Böse, D;Baum, A;Santoro, V;Chetta, P;Schnitzer, R;Botesteanu, DA;Reiser, C;Kornigg, S;Knesl, P;Hörmann, A;Köferle, A;Corcokovic, M;Lieb, S;Scholz, G;Bruchhaus, J;Spina, M;Balla, J;Peric-Simov, B;Zimmer, J;Mitzner, S;Fett, TN;Beran, A;Lamarre, L;Gerstberger, T;Gerlach, D;Bauer, M;Bergner, A;Schlattl, A;Bader, G;Treu, M;Engelhardt, H;Zahn, S;Fuchs, JE;Zuber, J;Ettmayer, P;Pearson, M;Petronczki, M;Kraut, N;McConnell, DB;Solca, F;Neumüller, RA;
PMID: 35883003 | DOI: 10.1038/s43018-022-00412-y

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling. Our results suggest that HER2 exon 20 insertion-driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing WT EGFR, paving the way for clinical translation.
Long Non-coding RNA Linc-ROR Is Upregulated in Papillary Thyroid Carcinoma

Endocr Pathol.

2017 Dec 26

Zhang R, Hardin H, Huang W, Buehler D, Lloyd RV.
PMID: 29280051 | DOI: 10.1007/s12022-017-9507-2

Long non-coding RNAs (lncRNAs) may contribute to carcinogenesis and tumor progression by regulating transcription and gene expression. The role of lncRNAs in the regulation of thyroid cancer progression is being extensively examined. Here, we analyzed three lncRNAs that were overexpressed in papillary thyroid carcinomas, long intergenic non-protein coding RNA, regulator of reprogramming (Linc-ROR, ROR) PVT1 oncogene (PVT1), and HOX transcript antisense intergenic RNA (HOTAIR) to determine their roles in thyroid tumor development and progression. ROR expression has not been previously examined in thyroid carcinomas. Tissue microarrays (TMAs) of formalin-fixed paraffin-embedded tissue sections from 129 thyroid cases of benign and malignant tissues were analyzed by in situ hybridization (ISH), automated image analysis, and real-time PCR. All three lncRNAs were most highly expressed in the nuclei of PTCs. SiRNA experiments with a PTC cell line, TPC1, showed inhibition of proliferation with siRNAs for all three lncRNAs while invasion was inhibited with siRNAs for ROR and HOTAIR. SiRNA experiments with ROR also led to increased expression of miR-145, supporting the role of ROR as an endogenous miR-145 sponge. After treatment with TGF-β, there was increased expression of ROR, PVT1, and HOTAIR in the PTC1 cell line compared to control groups, indicating an induction of their expression during epithelial to mesenchymal transition (EMT). These results indicate that ROR, PVT1, and HOTAIR have important regulatory roles during the development of PTCs.

Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion

Science advances

2023 Feb 03

Sun, C;Ye, Y;Tan, Z;Liu, Y;Li, Y;Hu, W;Liang, K;Egranov, SD;Huang, LA;Zhang, Z;Zhang, Y;Yao, J;Nguyen, TK;Zhao, Z;Wu, A;Marks, JR;Caudle, AS;Sahin, AA;Gao, J;Gammon, ST;Piwnica-Worms, D;Hu, J;Chiao, PJ;Yu, D;Hung, MC;Curran, MA;Calin, GA;Ying, H;Han, L;Lin, C;Yang, L;
PMID: 36724291 | DOI: 10.1126/sciadv.add6995

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.
Oncogenic Kras G12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 + T cells dependent manner

bioRxiv : the preprint server for biology

2023 Feb 18

Mahadevan, KK;McAndrews, KM;LeBleu, VS;Yang, S;Lyu, H;Li, B;Sockwell, AM;Kirtley, ML;Morse, SJ;Moreno Diaz, BA;Kim, MP;Feng, N;Lopez, AM;Guerrero, PA;Sugimoto, H;Arian, KA;Ying, H;Barekatain, Y;Kelly, PJ;Maitra, A;Heffernan, TP;Kalluri, R;
PMID: 36824971 | DOI: 10.1101/2023.02.15.528757

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRAS G12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras G12D mutant protein. Here we explore the impact of Kras G12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8 + T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8 + T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.
A Phase I, Multicenter, Dose-Escalation Study of the Oral Selective FGFR inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations.

Clin Cancer Res.

2019 Feb 11

Voss MH, Hierro C, Heist RS, Cleary JM, Meric-Bernstam F, Tabernero J, Janku F, Gandhi L, Iafrate AJ, Borger DR, Ishii N, Hu Y, Kirpicheva Y, Nicolas-Metral V, Pokorska-Bocci A, Vaslin Chessex A, Zanna C, Flaherty KT, Baselga J.
PMID: 30745300 | DOI: 10.1158/1078-0432.CCR-18-1959

Abstract

PURPOSE:

To investigate tolerability, efficacy, and pharmacokinetics/-dynamics (PK/PD) of Debio 1347, a selective fibroblast growth factor receptor (FGFR) Inhibitor.

EXPERIMENTAL DESIGN:

This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first 4 weeks on treatment, PK/PD post-first dose and after 4 weeks.

RESULTS:

Seventy-one patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had 6 DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, stomatitis). The maximum tolerated dose was not reached, but dermatological toxicity became sometimes dose-limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, three with FGFR fusions, demonstrated partial responses, 10 additional patients tumor size regressions of ≤30%. Plasma half-life was 11.5 h. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.

CONCLUSIONS:

Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C-driven cancers by addressing intrinsic and acquired resistance

bioRxiv : the preprint server for biology

2023 Jan 23

Thatikonda, V;Lu, H;Jurado, S;Kostyrko, K;Bristow, CA;Bosch, K;Feng, N;Gao, S;Gerlach, D;Gmachl, M;Lieb, S;Jeschko, A;Machado, AA;Marszalek, ED;Mahendra, M;Jaeger, PA;Sorokin, A;Strauss, S;Trapani, F;Kopetz, S;Vellano, CP;Petronczki, M;Kraut, N;Heffernan, TP;Marszalek, JR;Pearson, M;Waizenegger, I;Hofmann, MH;
PMID: 36747713 | DOI: 10.1101/2023.01.23.525210

Efforts to improve the anti-tumor response to KRAS G12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRAS G12C inhibitor (KRAS G12C i) to those induced by KRAS G12C i alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRAS G12C i induces an anti-tumor response stronger than that observed with KRAS G12C i alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRAS G12C i treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRAS G12C i-resistant CRC models. Our findings position KRAS G12C plus SOS1 inhibition therapy as a promising strategy for treating both KRAS G12C -mutated tumors as well as for addressing acquired resistance to KRAS G12C i.
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Description
sense
Example: Hs-LAG3-sense
Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron#
Example: Mm-Htt-intron2
Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
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Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)
A mixture of multiple probe sets targeting multiple genes or transcripts
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Example: Hs-PDGFB-No-XMm
Does not cross detect with the species (Sp)
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Example: Rn-Pde9a-XMm
designed to cross detect with the species (Sp)
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Example: Mm-Islr-O1
Alternative design targeting different regions of the same transcript or isoforms
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Example: Hs-SLC31A-CDS
Probe targets the protein-coding sequence only
EnEmProbe targets exons n and m
En-EmProbe targets region from exon n to exon m
Retired Nomenclature
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Example: Hs-LEPR-tv1
Designed to target transcript variant n
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Example: Hs-ACVRL1-ORF
Probe targets open reading frame
UTR
Example: Hs-HTT-UTR-C3
Probe targets the untranslated region (non-protein-coding region) only
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Example: Hs-GNRHR-5UTR
Probe targets the 5' untranslated region only
3UTR
Example: Rn-Npy1r-3UTR
Probe targets the 3' untranslated region only
Pan
Example: Pool
A mixture of multiple probe sets targeting multiple genes or transcripts

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Newark, CA 94560
Toll Free: 1 (877) 576-3636
Phone: (510) 576-8800
Fax: (510) 576-8798

 

Bio-Techne

19 Barton Lane  
Abingdon Science Park
Abingdon
OX14 3NB
United Kingdom
Phone 2: +44 1235 529449
Fax: +44 1235 533420

 

Advanced Cell Diagnostics China

20F, Tower 3,
Raffles City Changning Office,
1193 Changning Road, Shanghai 200051

021-52293200
info.cn@bio-techne.com
Web: www.acdbio.com/cn

For general information: Info.ACD@bio-techne.com
For place an order: order.ACD@bio-techne.com
For product support: support.ACD@bio-techne.com
For career opportunities: hr.ACD@bio-techne.com

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