Dr Rishabh Jain@DrRishabhOnco
🚀 KRAS: From “Undruggable” to the Hottest Target in Oncology 🔥🧬
KRAS is the most mutated oncogene in cancer - yet for decades it was “undruggable.”
2025 marks a turning point.
A brand-new Signal Transduction & Targeted Therapy review lays out the ENTIRE evolution:
• Why KRAS drives PDAC, CRC, NSCLC
• Why G12C inhibitors work but only partly
• Why resistance is inevitable
• What the next wave of KRAS therapies looks like
🔑 Key takeaways:
🧩 KRAS mutations = ~30% of all cancers
– PDAC: 80–90%
– CRC: ~40%
– NSCLC: ~20% (G12C dominant)
🧬 Approved “OFF-state” inhibitors:
•Sotorasib
•Adagrasib
➡️ ORR ~30–40%, PFS ~6 months.
➡️ Resistance? Guaranteed.
🔥 Major resistance mechanisms:
– Secondary KRAS mutations (Y96D/S, G13D, A59…)
– RTK pathway upregulation
– EMT & squamous transformation
– KRAS amplification
– KEAP1/STK11/TP53 co-mutation biology
💡 The future = multi-modal KRAS targeting:
– Pan-RAS inhibitors
– G12D inhibitors (MRTX1133-like)
– SOS1/SHP2 inhibitors combos
– KRAS degraders (PROTACs)
– KRAS vaccines & cell therapies
– RNA & antisense therapeutics
🧠 The review beautifully shows KRAS as a signaling “master switch” with MAPK, PI3K, Ral, RAC1, Hippo/YAP-TAZ crosstalk explaining why single-agent inhibition fails.
🎯 Bottom line:
KRAS is no longer undruggable - it’s just very hard to drug.
The next breakthroughs will come from combos + pan-KRAS + epigenetic modulation + TME targeting.
🔖 Save this - it’s THE 2025 roadmap for KRAS-targeted therapy.
📖 Full paper cited below.
#OncoTwitter #MedTwitter #LCSM #GIOnc #TargetedTherapy @myESMO @OncoAlert @ESMO_Open
