''KRAS'' (
Kirsten
Kirsten is both a given name and a surname.
Given name
Kirsten is a female given name. It is a Scandinavian form of the names Christina and Christine.sarcoma
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal ( connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sar ...
virus) is a gene that provides instructions for making a protein called K-Ras, a part of the
RAS/MAPK pathway
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling m ...
. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (
proliferate) or to mature and take on specialized functions (
differentiate). It is called ''KRAS'' because it was first identified as a viral
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. in the
Kirsten RAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so , when found in a cellular genome, is called a
proto-oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. .
The K-Ras protein is a
GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
, a class of
enzymes which convert the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecule ...
guanosine triphosphate (GTP) into
guanosine diphosphate (GDP). In this way the K-Ras protein acts like a
switch
In electrical engineering, a switch is an electrical component that can disconnect or connect the conducting path in an electrical circuit, interrupting the electric current or diverting it from one conductor to another. The most common type of ...
that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the nucleus.
The
gene product
A gene product is the biochemical material, either RNA or protein, resulting from expression of a gene. A measurement of the amount of gene product is sometimes used to infer how active a gene is. Abnormal amounts of gene product can be correlate ...
of ''KRAS'', the K-Ras protein, was first found as a p21 GTPase.
Like other members of the
ras subfamily of GTPases, the K-Ras protein is an early player in many
signal transduction pathways. K-Ras is usually tethered to
cell membranes because of the presence of an
isoprene group on its
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. There are two protein products of the ''KRAS'' gene in mammalian cells that result from the use of alternative
exon 4 (exon 4A and 4B respectively): K-Ras4A and K-Ras4B. These proteins have different structures in their C-terminal region and use different mechanisms to localize to cellular membranes, including the
plasma membrane.
Function
KRAS acts as a molecular on/off switch, using
protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...
. Once it is
allosterically
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
activated, it recruits and activates proteins necessary for the propagation of
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regul ...
s, as well as other
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
receptors like
c-Raf
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the ''RAF1'' gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase ...
and
PI 3-kinase. KRAS
upregulates the
GLUT1
Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the ''SLC2A1'' gene. GLUT1 facilitates the transport of glucose across ...
glucose transporter, thereby contributing to the
Warburg effect in cancer cells.
KRAS binds to
GTP in its active state. It also possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide, converting it to
GDP
Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is ofte ...
. Upon conversion of GTP to GDP, KRAS is deactivated. The rate of conversion is usually slow, but can be increased dramatically by an accessory protein of the
GTPase-activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are ...
(GAP) class, for example
RasGAP
RAS p21 protein activator 1 or RasGAP (Ras GTPase activating protein), also known as RASA1, is a 120- kDa cytosolic human protein that provides two principal activities:
* Inactivation of Ras from its active GTP-bound form to its inactive GDP-bo ...
. In turn, KRAS can bind to proteins of the
Guanine Nucleotide Exchange Factor
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated struc ...
(GEF) class (such as
SOS1
Son of sevenless homolog 1 is a protein that in humans is encoded by the ''SOS1'' gene.
Function
SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with RAS proteins to phosphorylate GDP into GTP, or from an inactive state to an ...
), which forces the release of bound nucleotide (GDP). Subsequently, KRAS binds GTP present in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
and the GEF is released from ras-GTP.
Other members of the Ras family include:
HRAS
GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 ...
and
NRAS. These proteins all are regulated in the same manner and appear to differ in their sites of action within the cell.
Clinical significance when mutated
This
proto-oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. is a Kirsten ras
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. homolog from the mammalian Ras gene family. A single amino acid substitution, and in particular a single nucleotide substitution, is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including
lung adenocarcinoma
Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to d ...
, mucinous adenoma,
ductal carcinoma
Ductal carcinoma is a type of tumor that primarily presents in the ducts of a gland.
Types include:
* Mammary
**Ductal carcinoma in situ
**Invasive ductal carcinoma
* Pancreatic ductal carcinoma
Pancreatic cancer arises when cells in the p ...
of the
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
and
colorectal cancer.
Several
germline KRAS mutations have been found to be associated with
Noonan syndrome
Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored ...
and
cardio-facio-cutaneous syndrome.
Somatic ''KRAS'' mutations are found at high rates in
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
s, colorectal cancer,
pancreatic cancer and
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...
.
Colorectal cancer
The impact of KRAS mutations is heavily dependent on the order of mutations. Primary ''KRAS'' mutations generally lead to a self-limiting hyperplastic or borderline lesion, but if they occur after a previous
APC mutation it often progresses to cancer.
KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.
KRAS mutation is predictive of a very poor response to
panitumumab
Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as ''EGF receptor'', ''EGFR'', ''ErbB-1'' and ''HER1'' in humans).
Panitumumab is manufactured by ...
(Vectibix) and
cetuximab
Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal a ...
(Erbitux) therapy in colorectal cancer.
Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the
EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occurs in 30%–50% of colorectal cancers. Studies show patients whose tumors express the mutated version of the ''KRAS'' gene will not respond to cetuximab or panitumumab.
Although presence of the wild-type (or normal) ''KRAS'' gene does not guarantee that these drugs will work, a number of large studies
have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study, published in 2009, patients with the wild-type ''KRAS'' gene treated with Erbitux plus chemotherapy showed a response rate of up to 59% compared to those treated with chemotherapy alone. Patients with the ''KRAS'' wild-type gene also showed a 32% decreased risk of disease progression compared to patients receiving chemotherapy alone.
Emergence of KRAS mutations is a frequent driver of acquired resistance to
cetuximab
Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal a ...
anti-EGFR therapy in colorectal cancers. The emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression. It suggests to perform an early initiation of a
MEK inhibitor A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2.
They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers. (See MAPK/ERK pathway#Clinical sign ...
as a rational strategy for delaying or reversing drug resistance.
''KRAS'' amplification
''KRAS'' gene can also be
amplified in colorectal cancer. Tumors or cell lines harboring this genetic lesion are not responsive to
EGFR inhibitors. Although KRAS amplification is an infrequent event in colorectal cancer, it might be responsible for precluding response to anti-
EGFR treatment in some patients.
Amplification of wild-type Kras has also been observed in ovarian, gastric, uterine, and lung cancers.
Lung cancer
Whether a patient is positive or negative for a mutation in the
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor rece ...
(EGFR) will predict how patients will respond to certain EGFR antagonists such as
erlotinib
Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) ...
(Tarceva) or
gefitinib
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targ ...
(Iressa). Patients who harbor an EGFR mutation have a 60% response rate to erlotinib. However, the mutation of KRAS and EGFR are generally mutually exclusive.
Lung cancer patients who are positive for KRAS mutation (and the EGFR status would be wild type) have a low response rate to erlotinib or gefitinib estimated at 5% or less.
Different types of data including mutation status and gene expression did not have a significant prognostic power.
No correlation to survival was observed in 72% of all studies with KRAS sequencing performed in non-small cell lung cancer (NSCLC).
However, KRAS mutations can not only affect the gene itself and the expression of the corresponding protein, but can also influence the expression of other downstream genes involved in crucial pathways regulating cell growth, differentiation and apoptosis. The different expression of these genes in ''KRAS''-mutant tumors might have a more prominent role in affecting patient's clinical outcomes.
A 2008 paper published in ''
Cancer Research
Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure.
Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate and ...
'' concluded that the in vivo administration of the compound oncrasin-1 "suppressed the growth of K-ras mutant human lung tumor
xenografts
Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograft ...
by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity", and that the "results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents which effectively kill K-Ras mutant cancer cells."
''KRAS'' testing
In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-
EGFR monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
drugs indicated for treatment of metastatic colorectal cancer,
panitumumab
Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as ''EGF receptor'', ''EGFR'', ''ErbB-1'' and ''HER1'' in humans).
Panitumumab is manufactured by ...
(Vectibix) and
cetuximab
Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal a ...
(Erbitux), to include information about ''KRAS'' mutations.
In 2012, the FDA also cleared
QIAGEN
QIAGEN N.V., the global corporate headquarter of the QIAGEN group, is located in Venlo, The Netherlands. Furthermore, European, American, and Asia regional headquarters are located in respectively Hilden, Germany, Maryland United States, and Sh ...
's
therascreen ''KRAS'' test, which is a genetic test designed to detect the presence of seven mutations in the ''KRAS'' gene in colorectal cancer cells. This test is used to aid physicians in identifying patients with metastatic colorectal cancer for treatment with Erbitux. The presence of KRAS mutations in colorectal cancer tissue indicates that the patient may not benefit from treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.
As a drug target
Driver mutations in KRAS underlie the pathogenesis of up to 20% of human cancers.
Hence KRAS is an attractive drug target, however lack of obvious binding sites has hindered pharmaceutical development.
One potential drug interaction site is where GTP/GDP binds. However, due to the extraordinarily high affinity of GTP/GDP for this site, it is unlikely that drug-like
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
inhibitors could compete with GTP/GDP binding. Other than where GTP/GDP binds, there are no obvious high affinity binding sites for small molecules.
G12C mutation
![KRAS protein G12C mutant with GDP and sotorasib 6OIM](https://upload.wikimedia.org/wikipedia/commons/9/93/KRAS_protein_G12C_mutant_with_GDP_and_sotorasib_6OIM.png)
One fairly frequent driver mutation is KRAS
G12C which is adjacent a shallow binding site. This has allowed the development of
electrophilic KRAS inhibitors that can form irreversible
covalent bonds with
nucleophilic
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
sulfur atom of Cys-12 and hence selectively target KRAS
G12C and leave wild-type KRAS untouched.
One KRAS
G12C mutant
covalent inhibitor,
sotorasib (AMG 510,
Amgen
Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was established in T ...
) has been approved for the treatment of
non-small cell lung cancer
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...
(NSCLC) by the U.S. FDA in 2021, becoming the first KRAS inhibitor to reach the market and enter clinical use.
A second,
adagrasib
Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer. Adagrasib is an inhibitor of the RAS GTPase family. It is taken by mouth. It is being developed by Mirati Therapeutics.
The mo ...
(MRTX-849,
Mirati Therapeutics
Mirati Therapeutics is an American targeted oncology company that focuses on the development of cancer therapeutics.
History
Mirati Therapeutics works largely in KRAS-mutation inhibition, and developing treatments for tumors that contain it. The ...
) while JNJ-74699157 (also known as ARS-3248,
Wellspring Biosciences/
Janssen) has received an
investigational new drug (IND) approval to start clinical trials.
An
antisense oligonucleotide
Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small bits of nucleic acids ...
(ASO) targeting KRAS, AZD4785 (
AstraZeneca
AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includi ...
/
Ionis Therapeutics), completed a phase I study but was discontinued from further development because of insufficient
knockdown of the target.
G12D mutation
The most common ''KRAS'' mutation is G12D which i
estimatedto be present in up to 37% pancreatic cancers and over 12% of colorectal cancers. Normally amino acid position 12 of the KRAS protein is occupied by glycine but in G12D it is occupied by aspartic acid.
There are currently no commercial drug candidates targeting the KRAD G12D mutation that have entered the clinical phase of development. The first clinical trial of a novel gene therapy targeting KRAS G12D is currently recruiting patients and is sponsored by the National Cancer Institute.
There are a number of drug candidates in preclinical stages of development targeting the KRAD G12D mutation.
Mirati therapeutics
Mirati Therapeutics is an American targeted oncology company that focuses on the development of cancer therapeutics.
History
Mirati Therapeutics works largely in KRAS-mutation inhibition, and developing treatments for tumors that contain it. The ...
has stated in the past it is seeking
investigational new drug (IND) approval in H1:2021 to start clinical trials. Revolution Medicines is currently exploring a small molecule therapy and has reporte
anti-tumor activity in KRAS-G12D mutant tumor modelsVRise Therapeuticshas reported progress in preclinical development of a novel KRAS G12D inhibitor.
Interactions
KRAS has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
C-Raf
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the ''RAF1'' gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase ...
,
*
PIK3CG
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform is an enzyme that in humans is encoded by the ''PIK3CG'' gene.
Function
This gene encodes a protein that belongs to the pi3/pi4-kinase family of proteins. The gene p ...
,
*
RALGDS
Ral guanine nucleotide dissociation stimulator is a protein that is encoded by the ''RALGDS'' gene in humans.
Interactions
RALGDS has been shown to interact with:
* Arrestin beta 1,
* Arrestin beta 2,
* HRAS,
* KRAS,
* MRAS,
* RAP1A,
* R ...
,
and
* RASSF2
Ras association domain-containing protein 2 is a protein that in humans is encoded by the ''RASSF2'' gene.
This gene encodes a protein that contains a Ras association domain. Similar to its cattle and sheep counterparts, this gene is located near ...
.
* Calmodulin
References
Further reading
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External links
KRAS Reference Standards
- Learn more about KRAS Reference Controls
GeneReviews/NCBI/NIH/UW entry on Cardiofaciocutaneous Syndrome
GeneReviews/NCBI/NIH/UW entry on Noonan syndrome
*
*
{{Acid anhydride hydrolases
Oncogenes