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KRAS – Gene, Mutation and Role in Cancer

KRAS is a human gene encoding a key signaling protein. Mutations in the KRAS gene play a central role in the development of several types of cancer.

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Things worth knowing about "KRAS"

KRAS is a human gene encoding a key signaling protein. Mutations in the KRAS gene play a central role in the development of several types of cancer.

What is KRAS?

KRAS (Kirsten Rat Sarcoma Viral Proto-Oncogene) is a proto-oncogene that encodes a small GTP-binding protein. This protein is a central component of signaling pathways that regulate cell growth, cell division, and cell survival. KRAS belongs to the family of RAS GTPases and functions as a molecular switch: in its active state it is bound to GTP (guanosine triphosphate), and in its inactive state to GDP (guanosine diphosphate). Mutations in the KRAS gene can permanently lock this switch in the active position, thereby triggering uncontrolled cell growth.

Biological Function

The KRAS protein plays a pivotal role in several intracellular signaling pathways:

MAPK/ERK pathway: Regulates cell proliferation and differentiation.
PI3K/AKT pathway: Controls cell survival and metabolic processes.
RAL pathway: Influences membrane transport and cell division.

Under normal conditions, KRAS is inactivated by GTPase-activating proteins (GAPs) once the cell growth signal is no longer required. In mutated KRAS proteins, this inactivation is impaired, leading to persistent activation of downstream signaling.

KRAS Mutations and Cancer

Mutations in the KRAS gene are among the most common oncogenic mutations in humans, occurring in approximately 25–30 % of all human tumors. KRAS mutations are particularly prevalent in the following cancer types:

Pancreatic cancer: Mutations in up to 90 % of cases
Colorectal cancer: Mutations in approximately 40 % of cases
Non-small cell lung cancer (NSCLC): Mutations in approximately 30 % of cases

The most common mutation hotspots are located at codons 12 and 13 of the KRAS gene. One of the most clinically significant variants is the KRAS G12C mutation, in which glycine is replaced by cysteine.

Diagnosis

Detection of KRAS mutations is typically performed using molecular genetic analysis methods:

PCR-based methods: Allele-specific PCR or digital PCR
Next-Generation Sequencing (NGS): Allows simultaneous analysis of multiple mutations
Liquid biopsy: Detection of circulating tumor DNA (ctDNA) in the blood
Immunohistochemistry (IHC): Rarely used for KRAS but can serve as a complementary method

KRAS testing is part of standard diagnostics for various cancers, as the result directly influences treatment decisions.

Clinical Relevance and Treatment

For a long time, KRAS was considered an undruggable target because no suitable binding sites for small molecules could be identified. However, this has changed significantly in recent years:

KRAS G12C Inhibitors

With the development of Sotorasib (AMG 510) and Adagrasib (MRTX849), the first approved KRAS inhibitors became available in 2021 and 2022, respectively. These covalent inhibitors bind specifically to the KRAS G12C mutant protein and block its persistent activation. They are approved for patients with KRAS G12C-mutated non-small cell lung cancer.

KRAS Mutations as Predictive Biomarkers

In colorectal cancer, the presence of a KRAS mutation excludes the use of EGFR antibodies (e.g., cetuximab, panitumumab), as these therapies are not effective in KRAS-mutated tumors. KRAS testing is therefore mandatory before initiating such therapies.

Combination Therapies

Current research is investigating the combination of KRAS inhibitors with other targeted therapies (e.g., MEK inhibitors, SHP2 inhibitors) or immunotherapies to overcome resistance mechanisms and improve therapeutic efficacy.

References

Simanshu DK, Nissley DV, McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017;170(1):17–33. doi:10.1016/j.cell.2017.06.009
Fell JB et al. Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. Journal of Medicinal Chemistry. 2020;63(13):6679–6693.
Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nature Reviews Drug Discovery. 2016;15(11):771–785.

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