KRAS Gene Function
KRAS Proto-Oncogene, GTPase
Overview
KRAS is mutated in ~90% of pancreatic ductal adenocarcinomas, ~40% of colorectal cancers, and ~25% of lung adenocarcinomas — making it the most commonly mutated oncogene in human cancer. Codon 12 mutations (G12C, G12D, G12V) and G13D impair GTP hydrolysis, locking KRAS in the constitutively active state that drives RAF/MEK/ERK proliferation and PI3K/AKT survival signalling. G12C's unique cysteine enabled the first direct KRAS inhibitors: sotorasib and adagrasib, approved for KRAS G12C-mutant NSCLC. Adaptive resistance emerges through secondary KRAS mutations, allele switching, and bypass RTK upregulation — driving combination strategies with SHP2 and EGFR inhibitors. Non-G12C mutations (G12D, G12V) driving pancreatic and colorectal cancer remain harder to target.
Molecular Mechanism
Mechanism Summary
Oncogenic KRAS mutations (G12C, G12D, G12V, G12R) impair intrinsic GTPase activity and block GAP protein stimulation, locking KRAS permanently in the GTP-bound active state and constitutively driving RAF/MEK/ERK proliferation and PI3K/AKT/mTOR survival signalling. G12C's unique cysteine nucleophile enabled the first covalent KRAS inhibitors — sotorasib and adagrasib — which trap KRAS G12C in the inactive GDP-bound conformation via switch-II pocket binding. Non-G12C mutations (G12D, G12V) driving >70% of pancreatic KRAS cases lack the nucleophilic cysteine, motivating pan-RAS inhibitors, SHP2 inhibitors, and KRAS-targeted protein degraders.
Step-by-Step Mechanism
Growth factor receptor activation (e.g., EGFR) recruits GRB2-SOS to the membrane. SOS catalyses GDP→GTP exchange on KRAS, producing the active GTP-bound conformation.
GTP-KRAS undergoes conformational change in switch I (residues 30–38) and switch II (residues 59–76), creating an effector-binding surface recognised by RAF, PI3K, and RALGDS.
GTP-KRAS binds and activates BRAF (and CRAF), promoting RAF dimerisation and MEK1/2 phosphorylation at Ser217/Ser221. Active MEK phosphorylates ERK1/2 at Thr185/Tyr187, driving transcription of cyclin D1 and MYC.
Intrinsic GTPase activity of KRAS — accelerated by GAP proteins (NF1, RASA1) — hydrolyses GTP→GDP, returning KRAS to its inactive state and terminating signal.
Oncogenic G12C/G12D/G12V mutations insert a bulky residue at the GTPase catalytic site, sterically blocking GAP-stimulated GTP hydrolysis. KRAS remains GTP-locked, constitutively active.
Upstream Regulators
Catalyse GDP→GTP exchange to activate KRAS; recruited by GRB2 from RTK signalling
Stimulates intrinsic GTPase activity to return KRAS to GDP-bound state; tumour suppressor
Upstream receptors activating GRB2-SOS-KRAS signalling axis
Downstream Targets
Proliferation, differentiation, survival
Survival, metabolism, protein synthesis
Vesicle trafficking, exocytosis, mitosis
Key Post-Translational Modifications
Active conformation; effector binding enabled
Membrane anchorage required for signalling
Calmodulin binding; modulates membrane association
Disease Mechanism
Oncogenic KRAS mutations are among the earliest detectable events in pancreatic cancer (>90% of cases) and are found in ~40% of colorectal and ~25% of lung adenocarcinomas. Constitutive KRAS signalling drives metabolic reprogramming, immune evasion, and context-dependent resistance to EGFR-targeted therapy. Allele-specific G12C inhibitors (sotorasib, adagrasib) represent the first class of direct KRAS inhibitors after 40 years of failed attempts. Why KRAS-targeted therapy remains limited: (1) Sotorasib and adagrasib target only G12C (~13% of KRAS-mutant NSCLC; ~1% of pancreatic KRAS cases) by covalently trapping KRAS in the GDP-bound state — G12D, G12V, and G12R lack this nucleophile. (2) Adaptive resistance can arise through secondary KRAS mutations, KRAS G12C amplification, and bypass RTK upregulation. (3) Combination strategies are tumour-context dependent: anti-EGFR combinations are clinically validated in previously treated KRAS G12C-mutant metastatic colorectal cancer, while other vertical combinations remain under study. (4) In colorectal and pancreatic cancer, co-alterations such as TP53, CDKN2A, or SMAD4 loss can limit the durability of single-agent KRAS inhibition.
Database References
Key Pathways
- ·RAS/MAPK signaling
- ·PI3K-AKT signaling
- ·RAF/MEK/ERK cascade
- ·mTOR signaling
- ·KRAS G12C inhibitor resistance
Disease Associations
- ·Pancreatic ductal adenocarcinoma
- ·Colorectal cancer
- ·Lung adenocarcinoma
- ·Noonan syndrome
Research Activity
KRAS is an actively studied target: about 500+ clinical trials that mention it are currently recruiting on ClinicalTrials.gov. Trial activity reflects research interest, not proven benefit — designs, endpoints and populations vary widely.
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Functional Partners
Common Questions About KRAS
What does the KRAS gene do?
KRAS encodes a small GTPase that transmits signals from growth factor receptors to downstream kinase cascades including RAF/MEK/ERK and PI3K/AKT. It cycles between an inactive GDP-bound state and an active GTP-bound state, with intrinsic GTPase activity normally terminating the signal within seconds.
Why is KRAS mutated so often in pancreatic cancer?
KRAS mutations — predominantly G12D — are present in ~90% of pancreatic ductal adenocarcinomas and appear to be among the earliest initiating events. Oncogenic KRAS impairs GTPase activity, locking it in the active GTP-bound state, and drives a transcriptional programme strongly favoured by the pancreatic tissue context.
Is KRAS G12C targetable with drugs?
Yes — sotorasib and adagrasib are covalent inhibitors that exploit the unique cysteine at position 12 to irreversibly lock KRAS G12C in its inactive GDP-bound conformation. Both are approved for KRAS G12C-mutant NSCLC, representing the first direct KRAS inhibitors after decades of the protein being labelled undruggable.
Why do colorectal cancer patients need KRAS testing?
In metastatic colorectal cancer, activating RAS mutations predict lack of benefit from cetuximab or panitumumab because downstream signalling can continue despite receptor blockade. RAS testing is part of treatment selection in this defined setting; the relationship should not be generalised to every EGFR-directed drug, tumour type or combination.
How do sotorasib and adagrasib work against KRAS G12C, and how do they differ?
Both sotorasib and adagrasib are covalent inhibitors that exploit the unique cysteine at KRAS position G12C to form an irreversible bond with the switch-II pocket of GDP-bound KRAS, locking it in an inactive conformation. The key mechanistic difference is their binding kinetics and reach within the switch-II pocket: adagrasib has a longer half-life (~23 hours vs ~6 hours for sotorasib) and shows activity in brain metastases. Neither drug covers G12D, G12V, or other non-cysteine KRAS mutations. Both are FDA-approved for KRAS G12C-mutant NSCLC; adagrasib is additionally approved for colorectal cancer in combination with cetuximab.
Why is KRAS G12D still hard to target and what approaches are being tested?
Unlike G12C, the G12D mutation (aspartate substitution) does not provide a nucleophilic cysteine that can form a covalent bond with an inhibitor. G12D also has higher intrinsic GDP/GTP cycling rates than G12C, making non-covalent inhibitor binding less stable. Approaches in development include: MRTX1133 (non-covalent G12D-selective inhibitor in phase I/II trials), RAS(ON) multi-selective inhibitors (daraxonrasib/RMC-6236) that target the active GTP-bound state across multiple KRAS mutations including G12D, and KRAS degraders (PROTACs) that eliminate KRAS protein rather than inhibiting it.
What is adaptive resistance to KRAS G12C inhibitors and how is it being overcome?
Adaptive resistance to G12C inhibitors (sotorasib, adagrasib) emerges through multiple mechanisms within 6 months of treatment: secondary KRAS mutations (Y96D, H95D) disrupt the switch-II pocket covalent binding site; KRAS G12C amplification overwhelms inhibitor stoichiometry; allele switching converts G12C to a non-targetable G12D or G12V allele; and bypass RTK upregulation (EGFR, HER2, MET, FGFR) reactivates downstream MAPK/PI3K signalling independently of KRAS. Combination strategies under investigation include G12C inhibitors + SHP2 inhibitors (to block adaptive RAS reactivation through GEF feedback), + EGFR antibodies (cetuximab), and + MEK inhibitors to prevent ERK pathway reactivation during resistance.