Adaptive resistance to MEK and PI3K inhibition in pancreatic cancer cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Pancreatic Ductal Adenocarcinoma Cell Line, Epithelium Of Pancreatic Duct
DISEASE(S): Pancreas Adenocarcinoma
SUBMITTER: 
Juan Francisco Martinez-Aguilar
LAB HEAD: Juan F
PROVIDER: PXD039692 | Pride | 2025-03-10
REPOSITORIES: Pride
Dataset's files
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Project description:MEK and PI3K inhibition on pancreatic cancer cells has demonstrated the existence of intrinsic resistance. Therefore, a comprehensive proteome profiling is needed to understand the associated molecular phenotype. PANC-1 and MIA PaCa-2 cancer cells were studied by label-free data-independent acquisition (SWATH) mass spectrometry with extensive peptide fractionation to quantitate and reveal differential expression of several proteins between resistant and sensitive cells. Proteomic differences cover a broad scope of molecular processes and putative candidate proteins for drug response.
2025-03-10 | PXD016493 | Pride
Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.
2020-05-26 | PXD013988 | Pride
Project description:Although most thyroid tumours are benign, thyroid cancer represents the most common malignancy of the endocrine system, comprising mainly follicular and papillary thyroid carcinomas (FTC and PTC, respectively). Previous studies have shed some light on the molecular pathogenesis of thyroid cancer but there have not been any comprehensive mass spectrometry-based proteomic studies to reveal protein expression differences between thyroid tumours and the molecular alterations associated with tumour malignancy. We applied a label-free quantitative mass spectrometry analysis to compare normal thyroid tissue with the three most common tumours of the thyroid gland: follicular adenoma, follicular carcinoma and papillary carcinoma.
2017-05-03 | PXD002732 | Pride
Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al. A375 and 16R6-4 (an A375 derived GSK2118436 resistance clone) were treated for 24 hours with 0.1 micromolar GSK2118436, 1 micromolar GSK2118436, 0.01 micromolar GSK1120212, 0.1 micromolar GSK2118436 + 0.01 micromolar GSK1120212, or 1 micromolar GSK2118436 + 0.01 micromolar GSK1120212.
2012-02-01 | E-GEOD-35230 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with a 5 year-survival rate below 5%. Lack of curative treatment and failure of targeted therapies urge the need to identify novel efficient therapeutic strategy. Achievement of this goal will be obtained through the identification of diagnosis and prognosis biomarkers, identification of novel therapeutic targets and the knowledge of resistance mechanisms induced by these targeted therapies. PI3K/Akt/mTOR signalling, one of the most altered in cancers, is overactivated in pancreatic cancer and correlated with poor prognosis. In the Vertebrates, the family of class I phosphoinoitide-3-kinase (PI3K) includes four isoforms: p110α, p110β, p110δ and p110γ. Although they all perform the same biochemical reaction (phosphorylation of PIP2 in PIP3, a membrane lipid messenger), each isoform were demonstrated to have specific physiological roles. Global PI3K inhibitors are currently being tested in phase I/II clinical trials in advanced solid cancers, but show at maximal doses tolerated a limited therapeutic benefit. Isoform-selective PI3K inhibitors are currently the most promising agents because, at low doses, they are more efficient to inhibit one PI3K isoform, and thus, less toxic than pan-PI3K inhibitors. The objectives of this thesis are to determine isoform-specific PI3K roles and the therapeutic interest to target one or more isoforms in pancreatitis and PDAC, by the identification of isoform-specific pathways and the study of adaptive responses induced by targeting of one or all isoforms of PI3K. In a first part, my work has highlighted, validated and completed results obtained in the team, to demonstrate the significance of PI3K/Akt signalling in two physiological processes: chronic pancreatitis and initiation of pancreatic carcinogenesis. Precisely, the overactivation of PI3K/Akt pathway measured on human and murine chronic pancreatitis samples is correlated with a specific p110α activation gene expression signature. Moreover, genetic and pharmacologic inactivation of p110α during pancreatic chronic inflammation or cancerogenesis (by oncogenic Kras) prevents the formation of acino-ductal metaplasia, structures at the origin of pancreatic carcinogenesis initiation. Development of in vitro acino-ductal transdifferentiation protocol allowed me to demonstrate that only p110α is necessary at this initial step of pancreatic carcinogenesis by the regulation of Rho small GTPases, further regulating actin remodelling. In the second part, by a phosphoproteomic-based approach, I quantified PI3K downstream phosphorylation-regulated targets in a pancreatic cancer cell line treated or not by a pan- or selective PI3K inhibitor at different times. I demonstrated for the first time existence of targets, signalling pathways and adaptive responses regulated by each PI3K isoform. To conclude, all these results demonstrate the rational of combinatorial use of isoform-specific PI3K inhibitors in patients with pancreatic cancer for better clinical response
2022-02-28 | PXD008410 | Pride
Project description:Analysis of the effects of a dual specificity PI3K/mTOR inhibitor on two human ovarian cell lines, OV2008 and MCAS. Results provide insight into the adaptive response to PI3K/mTOR inhibition in matrix attached ovarian cancer cells. The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and thus represents an important target for cancer therapeutics. Here we show that dual inhibition of PI3K/mTOR in ovarian cancer 3D-spheroids leads to death of the inner matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance is associated with up-regulation of a cellular survival program that involves both FOXO-regulated transcription and a novel translational resistance mechanism resulting in specific up-regulation of IRES-mediated, cap-independent translation. Inhibition of any of several up-regulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to dual PI3K/mTOR inhibition. These results demonstrate that acute adaptive response to PI3K/mTOR inhibition resembles well-conserved adaptive response to nutrient and growth factor deprivation and how development of rational drug combinations can bypass resistance mechanisms. Total RNA was isolated 6h and 24h after treatment with 1 M-NM-<M NVP-BEZ235 or DMSO vehicle control from 3D grown structures
2012-03-13 | E-GEOD-28992 | 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. 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:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al.
2012-02-01 | GSE35230 | GEO
Project description:Phosphoinositide 3-kinase (PI3K) signaling activation is frequently observed in triple negative breast cancer, however, PI3K inhibitors have shown limited clinical activity. To investigate resistance mechanisms, we performed global transcriptome, proteome, phosphoproteome and kinome analysis of a panel of triple negative breast cancer patient derived xenograft models with varying responsiveness to buparlisib, a pan-PI3K inhibitor, for differentially expressed baseline and post-treatment biomarkers. Resistance was associated with incomplete inhibition of PI3K and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified additional candidates in association with buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAPK2K4 reduced both baseline and feedback MAPK/MEK signaling and enhanced buparlisib efficacy in vitro. Interestingly, we show that a complex ins/del in PIK3CA led to a change in buparlisib response in a NEK9/MAP2K4 dependent manner. In summary, our study indicates a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased global analyses in uncovering resistance mechanisms to targeted therapy.
2018-05-29 | GSE100567 | GEO
Project description:<p>Filip Mundt, Sandeep Rajput, Shunqiang Li, Kelly Ruggles, Arshag D. Mooradian, Philipp Mertins, Michael A. Gillette, Karsten Krug, et al., Cancer Res. 2018 May 15;78(10):2732-2746. doi: 10.1158/0008-5472.CAN-17-1990.</p><p>Activation of phosphoinositide 3-kinase (PI3K) signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib in vitro. A complex in/del frameshift in PIK3CA decreased sensitivity to buparlisib via NEK9/MAP2K4-dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased omic analyses in uncovering resistance mechanisms to targeted therapy.</p><p>Mass spectra files contributing to this study can be downloaded in the original instrument vendor format (see Data Sets below). Metadata files include protocols and mapping of specimens to TMT6 labels for each experiment.</p><p>The protein database used to analyze mass spectrometry data files is also provided below (RefSeq.20130727-Human.20130730-MouseNR.mm13.fasta). This file includes the RefSeq database containing 31,767 human proteins, 24,821 mouse proteins, and 85 additional contaminants (RefSeq release 60, 2013/7/27-2013/7/30).</p><ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S040">https://cptac-data-portal.georgetown.edu/cptac/s/S040</a> on 10/19/18</li></ul>
2018-10-19 | MSV000083050 | MassIVE