1. Introduction
The KRAS (Kirsten rat sarcoma viral oncogene homolog) gene is one of the most extensively studied oncogenes in human cancer. It encodes KRAS, a small guanosine triphosphatase (GTPase) belonging to the RAS family of signaling proteins, which also includes HRAS and NRAS. These proteins function as molecular switches that regulate essential cellular processes, including proliferation, differentiation, survival, and metabolism. Under physiological conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state, allowing cells to respond appropriately to extracellular growth signals.
Mutations in KRAS are among the most common oncogenic alterations in solid tumors, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. Most cancer-associated mutations occur at specific amino acid positions, especially codons 12, 13, and 61, disrupting normal regulatory mechanisms and promoting persistent activation of downstream signaling pathways. The biological consequences depend on the specific mutation, tissue context, and presence of additional genomic alterations.
For decades, KRAS was considered an exceptionally difficult therapeutic target because of its high affinity for guanine nucleotides, the absence of readily accessible binding pockets, and the complexity of its interactions with downstream effectors. However, advances in structural biology and medicinal chemistry have fundamentally changed this perspective. The development of inhibitors targeting KRAS G12C established that direct pharmacological inhibition of mutant KRAS is feasible, opening new opportunities for precision oncology.
Understanding the physiological functions of KRAS, the molecular mechanisms underlying its oncogenic activation, and the therapeutic strategies designed to inhibit its signaling is therefore essential for interpreting its clinical significance in modern cancer care.
References
All references below are verified publications indexed in NCBI PubMed.
1. Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129(7):1287–1292. DOI: 10.1242/jcs.182873. PubMed.
2. Prior IA, Hood FE, Hartley JL. The frequency of RAS mutations in cancer. Cancer Res. 2020;80(14):2969–2974. DOI: 10.1158/0008-5472.CAN-19-3682. PubMed.
3. Cox AD, Der CJ. Ras history: The saga continues. Small GTPases. 2010;1(1):2–27. DOI: 10.4161/sgtp.1.1.12178. PubMed.
4. Uprety D, Adjei AA. KRAS: From undruggable to a druggable cancer target. Cancer Treat Rev. 2020;89:102070. DOI: 10.1016/j.ctrv.2020.102070. PubMed.
5. Drizyte-Miller K, Talabi T, Somasundaram A, Cox AD, Der CJ. KRAS: the Achilles’ heel of pancreas cancer biology. J Clin Invest. 2025;135(16):e191939. DOI: 10.1172/JCI191939. PubMed.
These references support the introduction’s molecular, oncological, and therapeutic context. PubMed+3
Next: Part 2 — KRAS Physiology and Molecular Signaling. This section will examine KRAS structure, GDP/GTP cycling, regulation by GEFs and GAPs, and the RAF–MEK–ERK and PI3K–AKT–mTOR signaling pathways, with additional verified PubMed references.