Rishabh Jain, Medical Oncologist at AIIMS, shared a post on X:
“KRAS is no longer “undruggable”.
A new Cancer Cell review maps how KRAS inhibitors are reshaping therapy across lung, colorectal, pancreatic and other cancers, and what comes next.
Essentials
- RAS alterations drive ~20% of cancers worldwide
- KRAS is the most frequent RAS alteration
- KRAS G12C inhibitors proved direct RAS targeting works
Current reality
Sotorasib and adagrasib show meaningful activity in KRAS G12C NSCLC. CRC responses improve when combined with anti-EGFR therapy. Activity emerging in PDAC and other tumors.
Key challenge
Most patients eventually develop resistance via:
- On-target KRAS mutations
- MAPK pathway reactivation
- RTK feedback signaling
- Non-genetic adaptive escape
What’s next?
Next-generation strategies include:
- More potent G12C inhibitors
- KRAS G12D & multi-mutation inhibitors
- Isoform-selective and pan-RAS inhibitors
- Rational combination approaches
Takeaway: KRAS targeting has moved from breakthrough to optimization phase, with broader RAS inhibition now the next frontier. Full paper in comment.”
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