scholarly journals KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2429
Author(s):  
Meichen Gu ◽  
Yanli Gao ◽  
Pengyu Chang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Genomic Alteration ◽  
Pancreatic Carcinogenesis ◽  
Novel Method ◽  
Almost All ◽  
Lung Adenocarcinomas

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

scholarly journals Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

2021 ◽  
Author(s):  
Tatsunori Suzuki ◽  
Takahiro Kishikawa ◽  
Tatsuyuki Sato ◽  
Norihiko Takeda ◽  
Yuki Sugiura ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Biological Effects ◽  
Redox Balance ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Early Event ◽  
Autophagic Flux ◽  
Nutritional Interventions ◽  
Mutational Activation ◽  
Almost All

AbstractMutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.

scholarly journals Positive Crosstalk Between Hedgehog and NF-κB Pathways Is Dependent on KRAS Mutation in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuqiong Wang ◽  
Dan Wang ◽  
Yanmiao Dai ◽  
Xiangyu Kong ◽  
Xian Zhu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Kras Mutation ◽  
Biological Effects ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Hh Signaling

It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.

Heterogeneity of KRAS mutation in pancreatic ductal adenocarcinoma

Pancreatology ◽  
2015 ◽  
Vol 15 (3) ◽  
pp. S28
Author(s):  
Daisuke Hashimoto ◽  
Kota Arima ◽  
Akira Chikamoto ◽  
Katsunobu Taki ◽  
Risa Inoue ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Kras Mutation ◽  
Ductal Adenocarcinoma

scholarly journals Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy

2019 ◽  
Author(s):  
Zhikai Wang ◽  
Ran Yan ◽  
Jiayun Li ◽  
Ya Gao ◽  
Philip Moresco ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Transglutaminase 2 ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblast ◽  
Pancreatic Cancer Cells ◽  
Keratin 19

AbstractHow pancreatic ductal adenocarcinoma (PDA) cells stimulate CXCR4 to exclude T cells and resist T cell checkpoint inhibitors is not known. Here, we find that CXCL12, the ligand for CXCR4 that is produced by the cancer-associated fibroblast, “coats” human PDA and colorectal cancer cells as covalent heterodimers with keratin 19 (KRT19). Modeling the formation of the heterodimer with three proteins shows that KRT19 binds CXCL12 and transglutaminase-2 (TGM2), and that TGM2 converts the reversible KRT19-CXCL12 complex into a covalent heterodimer. We validate this model by showing that cancer cells in mouse PDA tumors must express KRT19 and TGM2 to become coated with CXCL12, exclude T cells, and resist immunotherapy with anti-PD-1 antibody. Thus, PDA cells have a cell-autonomous means by which they capture CXCL12 to mediate immune suppression, which is potentially amenable to therapy.One Sentence SummaryCancer cells in pancreatic ductal adenocarcinoma use transglutaminase-2 to assemble a coating comprised of covalent CXCL12-keratin 19 heterodimers that excludes T cells and mediates resistance to inhibition of the PD-1 T cell checkpoint.

scholarly journals Molecular characteristics of BRCA1/2 and PALB2 mutations in pancreatic ductal adenocarcinoma

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e000942
Author(s):  
Andreas Seeber ◽  
Kai Zimmer ◽  
Florian Kocher ◽  
Alberto Puccini ◽  
Joanne Xiu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Molecular Profile ◽  
Molecular Characteristics ◽  
Missense Mutations ◽  
Breast Cancers ◽  
Extensive Evaluation

IntroductionPoly-(ADP)-ribose polymerase (PARP) inhibitors are successfully used for treatment of BRCA-mutated (mut) breast cancers and are under extensive evaluation for BRCA- and PALB2-mutated pancreatic ductal adenocarcinoma (PDAC). However, the optimal treatment regimen for BRCA/PALB2-mutated PDCA has yet to be established. Moreover, limited data are available on the association of BRCA/PALB2 gene alterations with other comutations and immunological biomarkers.Material and methodsTumour samples of 2818 patients with PDAC were analysed for BRCA1/2 PALB2 mutations and other genes by next-generation sequencing (NGS) (MiSeq on 47 genes, NextSeq on 592 genes). TMB was calculated based on somatic non-synonymous missense mutations. MSI-H/dMMR was evaluated by NGS, and PD-L1 expression was determined using immunohistochemistry.ResultsIn 4.2% (n=124) of all PDAC samples BRCA mutations have been detected. BRCA2 mutations were more commonly observed than BRCA1 mutations (3.1%(n=89) vs 1.1% [n=35], p<0.0001). BRCA2 mutation was associated with an older age (64 vs 61 years for wild-type (wt), p=0.002) and PALB2 mutation was observed more frequently in female than in male patients. BRCA and PALB2 mutations were associated with MSI-H/dMMR compared with wt (BRCA: 4.8% vs 1.2%, p=0.002; PALB2: 6.7% vs 1.3 %, p=0.18), PD-L1 expression of >1.0% (BRCA: 21.8% vs wt 11.2%, p<0.001, PALB2: 0.0% vs 12.4 %, p=0.38) and high TMB (BRCA: mean 8.7 vs 6.5 mut/MB, p<0.001; PALB2: 10.6 mut/Mb vs 6.6 mut/Mb, p=0.0007). Also, PD-L1 expression and TMB differed between BRCA and PALB2 mutation and wt samples in MSS tumours (p<0.05). BRCA-mutated and PALB2-mutated PDACs were characterised by a different mutational profile than was observed in wt tumours.ConclusionsBRCA and PALB2 mutations were found in a significant subgroup of PDACs. These mutations were associated with a distinct molecular profile potentially predictive for response to immune-checkpoint inhibitor therapy. Therefore, these data provide a rationale to evaluate PARP inhibitors in combination with immune-checkpoint inhibitors in patients with BRCA/PALB2-mutated PDAC.

Homologous recombination repair gene mutations in Chinese pancreatic ductal adenocarcinoma patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16234-e16234
Author(s):  
Nengwen Ke ◽  
Maolin Yan ◽  
Xu Che ◽  
Yu Cheng ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Homologous Recombination ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Checkpoint Inhibitors ◽  
Gene Mutations ◽  
Ductal Adenocarcinoma ◽  
Homologous Recombination Repair ◽  
Common Mutation ◽  
Wild Type ◽  
Recombination Repair

e16234 Background: Pancreatic cancer (PC) is a highly malignant tumor with poor prognosis. Among them, pancreatic ductal adenocarcinoma (PDAC) accounts for 80-90% of pancreatic cancer. While, the treatment of PDAC has always been a clinical challenge. PDAC with mutations in homologous recombination repair (HRR) genes such as BRCA are particularly sensitive to platinum agents. The POLO study has shown that Olaparib was efficient and well-tolerated as maintenance therapy in patients with germline BRCA1/2 mutation and a metastatic PDAC controlled after a platinum-based induction chemotherapy. However, investigation of prevalence of HRR gene mutations in Chinese PDAC patients need to be well defined. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from PDAC patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations and tumor mutational burden (TMB) values were assessed. The association of HRR gene mutations with TMB was assessed. The testing was carried out by OrigiMed (Shanghai, China) witch a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Using targeted capture genomic sequencing, we assessed 98 PDAC patients for germline and somatic loss-of-function mutations in 14 genes, including BRCA1, BRCA2, and 12 other genes in the HR pathway. Results: In total, 98 PDAC patients were recruited including 48 females and 50 males with a median age of 58 (range 35-84). The most frequently mutated genes were KRAS (94%), TP53 (74%), CDKN2A (36%), SMAD4 (27%), GATA6 (9%) and ATM (5%). Mutation rates varied in pancreatic cancer signaling pathway: WNT (35.71%), PI3K (11.22%), HRR (11.22%), NOTCH (3.06%), FGF (2.04%). 2.04% (2/98) patients had high TMB (defined as ≥10 muts/Mb) with a median of 2.2 muts/Mb (0-47 mus/Mb). 34.69% (34/98) of the patients had one or more actionable genetic mutations. We identified that 11.2% (11/98) patients had at least one mutation in HRR genes. The most frequently mutated HRR genes were ATM (50%), BRCA1 (16.7%), BRCA2 (25%) and PALB2 (8.3%). The most common mutation type in HRR-related gene was truncation (75%, 9/12). HRR-related germline mutations in BRCA (71.43%, 5/7), ATM (28.57%, 2/7) were detected in seven patients, six of them with cancer related family history. We confirmed that patients with HRR mutations were younger than wild type HRR (52.6 years vs. 59.3 years, p < 0. 05). We demonstrated that patients with HRR mutations had a significantly higher TMB than patients with wild type HRR (median TMB: 3.4 vs. 1.8 muts/Mb, p < 0. 05). Conclusions: HRR gene alterations occurred in 11.2% of Chinese PDAC patients HRR pathway alterations are relatively frequent in PDAC patients and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

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