Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors
<p>Strategies to target mutant KRAS cells. The lack of efficient therapies targeting mutant KRAS tumors represents an unmet clinical need. Several strategies have already been tested or are currently under development. Inhibitors of KRAS downstream effector molecules (e.g., RAF, MEK, PI3K) did not result in significant clinical benefit as standalone treatments, but their use in combination with receptor tyrosine kinase (RTK) inhibition has been shown to induce favorable antitumoral responses. The development of KRAS direct inhibitors represents a major breakthrough in the field, particularly of those targeting specific mutant forms, such as the G12C mutation, which are currently in clinical trials. Moreover, several other strategies under study aim to identify synthetic lethal interactors of KRAS, to impair KRAS post-translational modifications interfering with its subcellular localization, and to hamper the mechanisms used by mutant cells to obtain nutrients and energy.</p> "> Figure 2
<p>KRAS-induced immune-suppressive microenvironment. Mutant (mut)KRAS cells have been associated with decreased major histocompatibility class I (MHCI) expression, representing an impaired capacity to present antigens. Furthermore, the upregulation of programmed cell death ligand 1 (PD-L1) leads to immune evasion by inhibiting T-cell recognition. In these cells, the expression and secretion of several inflammatory cytokines is also recognized as being increased. Chemokine C-X-C ligand 3 (CXCL3) binds to its receptor chemokine C-X-C receptor 2 (CXCR2) on myeloid-derived suppressor cells (MDSCs) contributing to the maintenance and recruitment of these immune suppressive cells. In addition, granulocyte macrophage colony-stimulating factor (GM-CSF) is responsible for the accumulation of MDSCs in the tumor microenvironment. Moreover, the increased secretion of interleukin (IL)-10 and Transforming growth factor beta 1 (TGFβ1) induce the conversion of CD4+ CD25− T-cells into FOXP3+/CTLA4+/CD122+ T regulatory cells (Tregs) promoting immune suppression.</p> ">
Abstract
:1. Introduction
2. Current Approaches to Target Mutant KRAS Cells
3. Exploring the Crosstalk between the Cancer Cell and the Tumor Microenvironment to Target Mutant KRAS Cancers
3.1. Targeting Mutant KRAS-Driven Effects that Shape the Cancer-Immune Cell Crosstalk
3.2. Targeting the Crosstalk between Mutant KRAS Tumor Cells and Cancer-Associated Fibroblasts
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CAFs | Cancer-associated Fibroblasts |
CRC | Colorectal Cancer |
CSFR1 | Colony Stimulating Factor 1 Receptor |
CTLA-4 | Cytotoxic T-lymphocyte-associated Protein 4 |
CXCL | Chemokine C-X-C Motif Ligand |
CXCR | C-X-C Chemokine Receptor |
EGFR | Epidermal Growth Factor Receptor |
ERBB | Erythroblastic Leukemia Viral Oncogene Homologue Receptors |
FAP | Fibroblast Activation Protein |
GDP | Guanosine diphosphate |
GLI1 | GLI family zinc finger 1 |
GM-CSF | Granulocyye Macrophage Colony-stimulating Factor |
GTP | Guanosine triphosphate |
Hh | Hedgehog |
HIF-1α | Hypoxia Inducible Factor 1 Subunit Alpha |
HRAS | Harvey Rat Sarcoma Viral Oncogene Homolog |
IGFR | Insulin-like Growth factor |
IL | Interleukin |
IRF2 | Interferon Regulatory factor 2 |
KRAS | Kirsten Rat Sarcoma Viral Oncogene Homolog |
MDSCs | Myeloid-derived Suppressor Cells |
MET | Hepatocyte Growth Factor Receptor |
MHC I | Major Histocompatibility Class I |
MMR | Mismatch Repair |
NRAS | Neuroblastoma Rat Sarcoma Viral Oncogene Homolog |
NSCLC | Nonsmall Cell Lung Cancer |
PD-1 | Programmed Cell Death Protein 1 |
PDAC | Pancreatic Ductal Adenocarcinoma |
PD-L1 | Programmed Cell Death Protein Ligand 1 |
RAS | Rat Sarcoma Viral Oncogene Homolog |
RTK | Receptor Tirosine Kinase |
SHH | Sonic Hedgehog |
STING | Stimulator of Interferon Genes |
TGFβ1 | Transforming Growth Factor Beta 1 |
TME | Tumor Microenvironment |
Tregs | T regulatory cells |
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Dias Carvalho, P.; Machado, A.L.; Martins, F.; Seruca, R.; Velho, S. Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors. Cancers 2019, 11, 2010. https://doi.org/10.3390/cancers11122010
Dias Carvalho P, Machado AL, Martins F, Seruca R, Velho S. Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors. Cancers. 2019; 11(12):2010. https://doi.org/10.3390/cancers11122010
Chicago/Turabian StyleDias Carvalho, Patrícia, Ana Luísa Machado, Flávia Martins, Raquel Seruca, and Sérgia Velho. 2019. "Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors" Cancers 11, no. 12: 2010. https://doi.org/10.3390/cancers11122010