Question 1

What does the KRAS gene do?

Accepted Answer

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.

Question 2

Why is KRAS mutated so often in pancreatic cancer?

Accepted Answer

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.

Question 3

Is KRAS G12C targetable with drugs?

Accepted Answer

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.

Question 4

Why do colorectal cancer patients need KRAS testing?

Accepted Answer

KRAS mutations predict resistance to anti-EGFR antibodies (cetuximab, panitumumab) in metastatic colorectal cancer, because mutant KRAS signals constitutively regardless of EGFR inhibition. Testing RAS mutation status is mandatory before prescribing these expensive agents to spare patients ineffective and toxic treatment.

Question 5

How do sotorasib and adagrasib work against KRAS G12C, and how do they differ?

Accepted Answer

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.

Question 6

Why is KRAS G12D still hard to target and what approaches are being tested?

Accepted Answer

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.

Question 7

What is adaptive resistance to KRAS G12C inhibitors and how is it being overcome?

Accepted Answer

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.

KRAS Gene Function

Overview

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