Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA240233 | ENA |
REPOSITORIES: ENA
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Project description:Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis and mitosis, offering attractive targets for anti-cancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors in KRAS mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and anti-tumor activity both in vitro and in vivo than effects observed by previously reported MEK inhibitor combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS mutant cancers by suppressing a newly discovered resistance mechanism. This experiment is designed to detect genes differentially expressed in the combination treatment compared to others SW480 cells were seeded in 10cm dishes and treated for 4h and 16h with DMSO, TNKS inhibitor (TNKSi : NVP-TNKS656), MEK inhibitor (MEKi : AZD6244) or the combination of both at 1uM final
2014-03-06 | E-GEOD-55624 | biostudies-arrayexpress
Project description:Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis and mitosis, offering attractive targets for anti-cancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors in KRAS mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and anti-tumor activity both in vitro and in vivo than effects observed by previously reported MEK inhibitor combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS mutant cancers by suppressing a newly discovered resistance mechanism. This experiment is designed to detect genes differentially expressed in the combination treatment compared to others
2014-03-06 | GSE55624 | GEO
Project description:KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.
2020-08-20 | GSE128385 | GEO
Project description:KRAS is one of the driver oncogenes in non-small cell lung cancer (NSCLC), but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and better control tumor growth and survival. We used microarrays to examine the MAPK signaling pathway suppression from tumor lungs of KRASG12C GEMM after continuous vs. pulsatile treatment of selumetinib.
2019-09-11 | GSE126202 | GEO
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance. In the study, we identified and evaluated biomarker for response to MEK inhibitor on colon cancer cells.
2015-08-13 | E-GEOD-71981 | biostudies-arrayexpress
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance.
2015-08-13 | GSE71981 | GEO
Project description:There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) + SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and CRC.
2017-08-01 | GSE99015 | GEO
Project description:Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can reveal unexpected synthetic lethal interactions and uncover biomarkers of drug sensitivity. Preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knock-in” mice showed that the MEK inhibitor PD0325901 (PD901) extended survival while the pan-phosphoinositide 3-kinase (PI3K) inhibitor GDC-0941 was ineffective. One outlier PD901-treated AML had a four-fold improvement in survival, and exhibited intrinsic drug resistance at relapse. This resistant leukemia arose from an evolutionary precursor of the dominant drug-sensitive AML, and KrasG12D was duplicated in both AML clones. Loss of wild-type (WT) Kras both enhanced the competitive fitness of the dominant clone and rendered it more sensitive to MEK inhibition. Similarly, colorectal cancer cell lines with loss of WT KRAS are more sensitive to MEK inhibitors, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized a heterozygous mutant HCT116 cells to drug treatment. In a large prospectively characterized cohort of tumors from patients with advanced and metastatic cancers, 642 of 1168 (55%) with KRAS mutations exhibited allelic imbalance. Together, these studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer, and can modulate competitive fitness and MEK dependency.
2016-12-22 | GSE92682 | GEO
Project description:Aberrant RAS/MAPK signaling, a common driver of oncogenesis, can be therapeutically targeted with clinically approved MEK inhibitors. Single agent therapy ultimately results in tumor outgrowth in most settings and combination therapies are required to achieve significant clinical benefit in most advanced cancers. Here we focus on identifying MEK inhibitor-based combination therapies in RAS-mutant neuroblastoma. Mutations that activate the RAS/MAPK signaling pathway, while rare at diagnosis, are more frequent in relapsed neuroblastoma. More than 50% of children with high-risk neuroblastoma ultimately relapse and treatment options for relapsed neuroblastoma are limited so most children with relapsed disease do not survive. Here we use a genome-scale CRISPR-Cas9 functional genomic screen to identify genes that, when lost, sensitize RAS-mutant neuroblastoma to MEK inhibition. We discover that loss of either CCNC or CDK8, two members of the mediator kinase module, sensitizes neuroblastoma to MEK inhibition. Furthermore, we demonstrate that small molecule kinase inhibitors of CDK8 improve response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors, suggesting that the addition of CDK8 inhibitors could improve clinical outcome. Using transcriptional profiling, we unexpectedly find that loss of CDK8 or CCNC antagonizes the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevents the compensatory upregulation of pro-growth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies.
2023-02-22 | GSE190178 | GEO
Project description:Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC), a deadly bile duct malignancy. FGFR kinase inhibitors (FGFRi) have shown promising efficacy against FGFR2+ ICC in clinical trials, leading to the regulatory approval of the ATP-competitive FGFR inhibitors, pemigatinib and infigratinib (BGJ398), for this subset of patients who failed standard treatment . However, the objective response rate (ORR) for each FGFR inhibitor (FGFRi) studied to date in FGFR2+ ICC is <45% and disease progression invariably arises within ~6-12 months. By employing high-throughput drug screens and signaling studies, we identified signaling feedback via the EGFR pathway as a major mediator of adaptive resistance to FGFR kinase inhibition in a set of patient-derived ICC models. To further gain insights into the synergistic effects of the EGFR/FGFR combination and address the mechanisms underlying the survival pathway reactivation, we performed RNA sequencing in our FGFR-driven ICC models (ICC21 and ICC10-6). For these studies, we treated FGFR2 fusion+ ICC cell lines ICC21/ICC10-6 with four conditions (DMSO/Infigratinib/Afatinib/Combo) for 4 hours followed by RNA sequencing.
2024-03-21 | E-MTAB-11324 | biostudies-arrayexpress