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Antigen Peptide Transporter 1 (TAP1) Promotes Resistance to MEK Inhibitors in Pancreatic Cancers.

ABSTRACT: Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors show limited benefit in Kirsten rat sarcoma (KRAS) mutant pancreatic cancer due to drug resistance. To identify mechanisms of resistance to MEK inhibitor (MEKi), we employed a differential expression analysis of MEKi-sensitive versus MEKi-resistant KRAS-mutant pancreatic cancer cell lines. Here, we report that the antigen peptide transporter 1 (TAP1) expression levels of MEKi-resistant cell lines were notably higher than those of MEKi-sensitive cell lines. Suppression of TAP1 significantly sensitized the MEKi-resistant pancreatic ductal adenocarcinoma (PDAC) cells to MEKi and induced higher apoptotic rate in vitro. Moreover, knockdown of TAP1 in MEKi-resistant tumor significantly decreased tumor growth in vivo. Consistently, overexpression of TAP1 in sensitive PDAC cells resulted in increased resistance to MEKi, both in vitro and in vivo. Mechanistic studies demonstrated that TAP1 promoted chemoresistance by enhancing the transport of MEKi out of PDAC cells, leading to reduced intracellular MEKi concentration and attenuated inhibition of KRAS signaling pathways. Moreover, TAP1 expression increased spheroid formation abilities of PDAC cells. These findings suggest that TAP1 could serve as a potential marker for predicting the response of patients to MEKi. Combination of TAP1 suppression and MEKi may provide a novel therapeutic strategy for PDAC treatment.

SUBMITTER: Li B

PROVIDER: S-EPMC9266799 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pancreatic cancer is an increasing cause of cancer related death worldwide. KRAS is the dominant oncogene in this cancer type and molecular rationale would indicate, that inhibitors of the downstream target MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular biomarkers that can help to define subgroups where MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical pancreatic cancer samples to identify the molecular subtypes of pancreatic cancer these cell lines represent. Luminescent cell viability assay was used to determine the sensitivity of cell lines to kinase inhibitors. Western blot was used to analyze the pathway activity of the examined cell lines. According to our cell viability and pathway activity data on these model cell lines only cells harboring the rare G12C KRAS mutation and low EGFR expression are sensitive to single MEK inhibitor (trametinib) treatment. The common G12D KRAS mutation leads to elevated baseline Akt activity, thus treatment with single MEK inhibitors fails. However, combination of MEK and Akt inhibitors are synergistic in this case. In case of wild-type KRAS and high EGFR expression MEK inhibitor induced Akt phosphorylation leads to trametinib resistance which necessitates for MEK and EGFR or Akt inhibitor combination treatment. In all we provide strong preclinical rational and possible molecular mechanism to revisit MEK inhibitor therapy in pancreatic cancer in both monotherapy and combination, based on molecular profile analysis of pancreatic cancer samples and cell lines. According to our most remarkable finding, a small subgroup of patients with G12C KRAS mutation may still benefit from MEK inhibitor monotherapy.

Project description:Transporter associated with antigen processing 1 (TAP1) is a transporter protein that represent tumor antigen in the MHC I or HLA complex. Any defect in the TAP1 gene resulting in inadequate tumor tracking. TAP1 influences multidrug resistance (MDR) in human cancer cell lines and hinders the treatment during chemotherapeutic. The association of TAP1 in cancer progression remains mostly unknown and further study of the gene in relation with cancer need to conduct. Thus, the study has designed to analyze the association between the TAP1 with cancer by computationally. The expression pattern of the gene has determined by using ONCOMINE, GENT2, and GEPIA2 online platforms. The protein level of TAP1 was examined by the help of Human Protein Atlas. Samples with different clinical outcomes were investigated to evaluate the expression and promoter methylation in cancer vs. normal tissues by using UALCAN server. The copy number alteration, mutation frequency, and expression level of the gene in different cancer were analyzed by using cBioPortal server. The PrognoScan and KM plotter platforms were used to perform the survival analysis and represented graphically. Additionally, pathway and gene ontology (GO) features correlated to the TAP1 gene were analyzed and presented by bar charts. After arranging the data in a single panel like correlating expression to prognosis, mutational and alterations characteristic, and pathways analysis, we observed some interesting insights that emphasized the importance of the gene in cancer progression. The study found the relationship between the TAP1 expression pattern and prognosis in different cancer tissues and shows how TAP1 affects the clinical characteristics. The analytical data presented in the study is vital to learn about the effect of TAP1 in tumor tissue, where previously studies showing contradicting expression of TAP1 in cancer tissue. The analyzed data can also be utilized further to evade the threats against chemotherapy. Overall, the study provided a new aspect to consider the role of TAP1 gene in cancer progression and survival status. KEY MESSAGES: • This study demonstrated, for the first time, a correlation between the TAP1 gene and tumor progression. • An upregulation of TAP1 mRNA was demonstrated in various cancer types. • This study reported a significant negative correlation for TAP1 gene expression and the survival rate in different cancer types.

Project description:Tumor escape is often associated with abnormalities in the surface expression of the human leukocyte antigen class I (HLA-I) antigens thereby limiting CD8+ cytotoxic T cell responses. This impaired HLA-I surface expression can be mediated by deficient expression of components of the antigen processing and presentation machinery (APM) due to epigenetic, transcriptional and/or post-transcriptional processes. Since a discordant mRNA and protein expression pattern of APM components including the peptide transporter associated with antigen processing 1 (TAP1) has been frequently described in tumors of distinct origin, a post-transcriptional control of APM components caused by microRNAs (miR) was suggested. Using an in silico approach, miR-200a-5p has been identified as a candidate miR binding to the 3' untranslated region (UTR) of TAP1. Luciferase reporter assays demonstrated a specific binding of miR-200a-5p to the TAP1 3'-UTR. Furthermore, the miR-200a-5p expression is inversely correlated with the TAP1 protein expression in HEK293T cells and in a panel of melanoma cell lines as well as in primary melanoma lesions. High levels of miR-200a-5p expression were associated with a shorter overall survival of melanoma patients. Overexpression of miR-200a-5p reduced TAP1 levels, which was accompanied by a decreased HLA-I surface expression and an enhanced NK cell sensitivity of melanoma cells. These data show for the first time a miR-mediated control of the peptide transporter subunit TAP1 in melanoma thereby leading to a reduced HLA-I surface expression accompanied by an altered immune recognition and reduced patients' survival.AbbreviationsAb: antibody; ACTB: β-actin; APM: antigen processing and presentation machinery; ATCC: American tissue culture collection; β2-m: β2-microglobulin; BSA: bovine serum albumin; CTL: cytotoxic T lymphocyte; FCS: fetal calf serum; FFL: firefly luciferase; FFPE: formalin-fixed paraffin-embedded; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HC: heavy chain; HLA: human leukocyte antigen; HLA-I: HLA class I; HRP: horseradish peroxidase; IFN: interferon; im-miR: immune modulatory miRNA; LMP: low molecular weight protein; luc: luciferase; MFI: mean fluorescence intensity; MHC: major histocompatibility complex; miR: microRNA; NC: negative control; NK: natural killer; NSCLC: non-small cell lung carcinoma; OS: overall survival; PBMC: peripheral blood mononuclear cells; RBP: RNA-binding proteins; RL: Renilla; RLU: relative light units; TAP: transporter associated with antigen processing; tpn: tapasin; UTR: untranslated region.

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Antigen Peptide Transporter 1 (TAP1) Promotes Resistance to MEK Inhibitors in Pancreatic Cancers.

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