Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma
Abstract
:1. Introduction
2. Pathobiology of Pancreatic Ductal Adenocarcinoma
3. KRAS Signaling Pathways in PDAC
4. Mutated KRAS and the Tumor Microenvironment
4.1. Inflammatory Chemokines, Cytokines, and Interleukin 6
4.2. Mutated KRAS Effect on the Surrounding Stromal Cells
4.3. Mutated KRAS Interaction with the Immune Cells
5. KRAS Mutation and Metabolic Reprogramming
6. KRAS Mutation in Patients with Diabetes Mellitus
6.1. Therapeutic Targets in KRAS-Mutated Pancreatic Cancer
6.2. Therapeutic Targets of KRAS Mutation in CAFs and Importance of Vitamin D Therapy
6.3. Modulating the Immune Status of PDAC Microenvironment
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Glossary and Abbreviations
AXL | Is a member of the TAM (Tyro3, Axl, MerTK) receptor tyrosine kinase family. It has been found to drive metastasis and cause immune suppression in different cancers including PDAC. |
CAFs | Cancer-associated fibroblasts. It can promote tumorigenic features by initiating the remodeling of the extracellular matrix by secreting cytokines. |
ERK | MEK–extracellular signal-regulated kinase. |
FoxM1 | Fork-head box M1. |
GAS6 | Growth arrest-specific gene 6 (GAS6). It has an important role in the stimulation of cell proliferation. |
IGF-1 | Insulin-like growth factor 1 (IGF1), is a hormone that plays an important role in childhood growth. Through inhibition of apoptosis, IGF-1 has been shown to promote cancer development. |
INK4a–ARF | Inhibitors of CDK4 (INK4). The INK4a–ARF locus on chromosome 9 is one of the sites mutated most frequently in human cancer. Two genes comprising over-lapping reading frames encoding p16 (INK4a) and p19 (ARF) have been discovered at this locus, and remarkably, both play an important role in regulating cell growth, survival, and senescence. |
KRAS | Kirsten rat sarcoma viral oncogene homolog (KRAS) gene: A gene that makes a protein that is involved in cell signaling pathways that control cell growth, cell maturation, and cell death. The natural, unchanged form of the gene is called wild-type KRAS. Mutated (changed) forms of the KRAS gene have been found in some types of cancer, including non-small-cell lung cancer, colorectal cancer, and pancreatic cancer. These changes may cause cancer cells to grow and spread in the body. |
MAPK | mitogen-activated protein kinase. |
MEK | MAPK kinase. |
MHC | The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. PDAC cells show a reduced expression of MHC-Class1 on their cell surface. |
mTOR | mechanistic target of rapamycin. |
MUC4 | Mucin4 is a large membrane-anchored glycoprotein that belongs to the mucin family. They play an important role in the protection of epithelial cells. Its overexpression has been seen in many types of carcinomas. |
NF-κB | Nuclear factor- κB. |
PI3K | phosphoinositide 3-kinase. |
PPP | pentose phosphate pathway. |
RAF | rapidly accelerated fibrosarcoma. |
SHH | Sonic Hedgehog (SHH), is one of the hedgehog pathways that play an important role in the regulation of embryonic development. It has been found to play an important role in tumor initiation and invasiveness. |
SMAD4 | Mothers against decapentaplegic homolog4 (SMAD4), also called DPC4, is an Intra-cellular messenger of TGF-β and shows an anti-tumor effect by inhibiting the cell growth. |
TCA | tricarboxylic acid. |
VDR | Vitamin D receptor. |
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Targets/Diseases | Drugs | Phase of Trial | Patients/ In Vivo/In Vitro | Outcomes | References |
---|---|---|---|---|---|
Targeting CXCR4 in PDAC | BL-8040 (CXCR4 inhibitor) plus pembrolizumab with or without 5-FU and liposomal irinotecan | Phase 2 | 80 Patients | Objective response rate | [90] NCT02826486 [91] |
Targeting AXL | (Nab-paclitaxel, Gemcitabine, Cisplatin) with or without BGB324 (Axl inhibitor) TP-0903 | Phase 1 and 2 Phase 1 | 74 Patients 177 Patients | Decreased tumor volume and increased cancer cell apoptosis | NCT03649321 [81] NCT02729298 [82] |
Metabolism in RAS-driven Pancreatic cancer. Stage II, III, IV pancreatic cancer | Trametinib, hydroxychloroquine | Phase 1 | 33 participants | Ongoing Results are not yet available | NCT03825289 |
Targeting autophagy/Metabolism in RAS-driven Pancreatic cancer. Metastatic pancreatic adenocarcinoma, stage IV pancreatic cancer | Hydroxychloroquine, binimetinib | Phase 1 | 39 participants | Ongoing Results are not yet available | NCT04132505 |
KRAS p.G12C Mutant Advanced Solid Tumors | AMG 510 (Sotorasib) Anti PD-1/L1 Midazolam | Phase 1 and 2 | 733 participants | Partial responses in two of four NSCLC patients, with stable disease achieved in the remaining two | NCT03600883 |
Multiple clinical trials are underway to assess the benefit of vitamin D treatment in PDAC | |||||
Multiple clinical trials are underway to assess the benefit of vitamin D treatment in PDAC | calcipotriol (a synthetic form of vitamin D) Combined Calcipotriol and gemcitabine treatment | In vivo In vivo | Reduced markers of inflammation and fibrosis in pancreatitis and human tumor strom aEnhanced the survival of the KPC (KRASLSL-G12D/+; Trp53LSL-R172H/+; Pdx-1-Cre) mouse model, ultimately increasing median animal survival by 57%. | NCT03472833 NCT03300921 NCT02754726 [87] | |
Targeting vitamin D receptor (VDR) /PDAC | Vitamin D receptor agonist paricalcitol plus gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer | Phase 2 | 112 Patients | Ongoing Results are not yet available |
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Hafezi, S.; Saber-Ayad, M.; Abdel-Rahman, W.M. Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma. Int. J. Mol. Sci. 2021, 22, 10219. https://doi.org/10.3390/ijms221910219
Hafezi S, Saber-Ayad M, Abdel-Rahman WM. Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma. International Journal of Molecular Sciences. 2021; 22(19):10219. https://doi.org/10.3390/ijms221910219
Chicago/Turabian StyleHafezi, Shirin, Maha Saber-Ayad, and Wael M. Abdel-Rahman. 2021. "Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma" International Journal of Molecular Sciences 22, no. 19: 10219. https://doi.org/10.3390/ijms221910219