KRAS

KRAS (

The K-Ras protein is a GTPase, a class of enzymes which convert the nucleotide guanosine triphosphate (GTP) into guanosine diphosphate (GDP). In this way the K-Ras protein acts like a switch 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

Other members of the Ras family include: HRAS and NRAS. These proteins all are regulated in the same manner and appear to differ in their sites of action within the cell.^{[citation needed]}

Clinical significance when mutated

This

Somatic KRAS mutations are found at high rates in leukemias, colorectal cancer,^[15] pancreatic cancer^[16] and lung cancer.^[17]

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

As of 2006, KRAS mutation was predictive of a very poor response to panitumumab (Vectibix) and cetuximab (Erbitux) therapy in colorectal cancer.^[21]

As of 2008, the most reliable way to predict whether a colorectal cancer patient will respond to one of the

As of 2009 although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies[23]^[24] had shown that cetuximab had 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.^[24]

As of 2012 it was known that emergence of KRAS mutations was a frequent driver of acquired resistance to cetuximab anti-EGFR therapy in colorectal cancers. The emergence of KRAS mutant clones can be detected non-invasively^[how?] months before radiographic progression. It suggests to perform an early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.^[25]

KRAS amplification

KRAS gene can also be

Whether a patient is positive or negative for a mutation in the epidermal growth factor receptor (EGFR) will predict how patients will respond to certain EGFR antagonists such as erlotinib (Tarceva) or gefitinib (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.^[29][30][31] 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.^[29]

Different types of data including mutation status and gene expression did not have a significant prognostic power.^[32] No correlation to survival was observed in 72% of all studies with KRAS sequencing performed in non-small cell lung cancer (NSCLC).^[32] 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.^[32]

A 2008 paper published in Cancer Research concluded that the in vivo administration of the compound oncrasin-1 "suppressed the growth of K-ras mutant human lung tumor xenografts 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."^[33]

Pancreatic cancer

Over 90% of

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs indicated for treatment of metastatic colorectal cancer, panitumumab (Vectibix) and cetuximab (Erbitux), to include information about KRAS mutations.^[40]

In 2012, the FDA cleared a genetic test by

As of 2014, driver mutations in KRAS were known to underlie the pathogenesis of up to 20% of human cancers.[42] Hence KRAS is an attractive drug target, but as of 2018 lack of obvious binding sites had hindered pharmaceutical development.^[43] One potential drug interaction site is where GTP/GDP binds, but due to the extraordinarily high affinity of GTP/GDP for this site, it appeared unlikely as of 2018 that drug-like small molecule inhibitors could compete with GTP/GDP binding. Other than where GTP/GDP binds, there are no obvious high affinity binding sites for small molecules.^[44]

G12C mutation

One fairly frequent driver mutation is KRAS^G12C which is adjacent a shallow binding site. As of 2019, this allowed the development of

A phase Ia/Ib dose escalation trial of the oral selective KRAS G12C inhibitor divarasib was published in 2023, where the drug was tested in non-small cell lung cancer, colorectal cancer, and other solid tumors with KRAS G12C mutations.^[55] It continues in phase I and II studies for several cancer types as of August 2023.^{[56][57][58][59]}

G12D mutation

The most common KRAS mutation is G12D which is estimated to 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.^[60]

As of 2023, there are no commercial drug candidates targeting the KRAS G12D mutation in the clinical phase of development.

A novel inhibitor finding strategy for mutated G12D KRAS molecules was described in.^[61] The KRAS mutations in the 12th residue position inhibit the bound of the regulatory GAP molecule to the mutated KRAS, causing uncontrolled cell growth. The novel strategy proposes finding small glue molecules, which attach the mutated KRAS to the GAP, prohibiting uncontrolled cell growth and restoring the normal function. For this goal a theoretical KRAS-GAP conformation was designed with a several Å gap between the molecules, and a high-throughput in silico docking was performed for finding gluing agents. As a proof of concept, two novel molecules were described with satisfying biological activity.

As of 2021, there were a number of drug candidates in

In 2021, the first clinical trial of a gene therapy targeting KRAS G12D was recruiting patients, sponsored by the National Cancer Institute.^[64]

In June 2022, a case report was published about a 71-year-old woman with metastatic pancreatic cancer after extensive treatment (

• C-Raf,^[66][67]
• PIK3CG,^[68]
• RALGDS,^[66][69] and
• RASSF2.^[70]
• Calmodulin^[71]

References