Inhibition of the RAS Pathway

... the RAS pathway inhibition is one of the most active and challenging fields in oncology. Because RAS mutations (KRAS, NRAS, HRAS) are among the most common oncogenic drivers in human cancer, therapeutic targeting has long been a “holy grail.” Here’s a detailed breakdown:

1. Why RAS is Hard to Target

• Structure problem: RAS proteins are small, globular, and lack deep hydrophobic pockets → difficult for small molecules to bind.

• High affinity for GTP/GDP: Picomolar affinity makes it nearly impossible to outcompete with drugs.

• Multiple isoforms: KRAS, HRAS, NRAS have overlapping but distinct functions and tissue distributions.

• Network redundancy: Even if RAS is inhibited, tumors may bypass through parallel pathways (PI3K, MAPK).

2. Direct RAS Inhibition

(A) KRAS G12C inhibitors

• Mutated cysteine (G12C) provides a unique reactive pocket near the Switch II region.

• Drugs:

  • Sotorasib (AMG 510) → FDA approved for KRAS G12C NSCLC (2021).

  • Adagrasib (MRTX849) → FDA approved (2022).

• Mechanism: Covalently bind to cysteine at codon 12 → trap KRAS in inactive GDP-bound state → block downstream MAPK signaling.

• Limitations: Resistance develops (secondary mutations, pathway reactivation, YAP/TEAD escape routes).

(B) Pan-RAS inhibitors

• Small molecules or peptides designed to block RAS–SOS interaction (e.g., BI-3406, MRTX1133 for KRAS G12D).

• MRTX1133 (preclinical) → first potent KRAS G12D inhibitor, a mutation common in pancreatic cancer.

 (C) RAS degradation (PROTACs)

• New approach: targeted protein degradation via ubiquitin ligase recruitment → KRAS destruction inside the cell.

3. Indirect Targeting of RAS Signaling

(A) Block RAS post-translational modification

• RAS needs farnesylation (lipid anchor) to attach to the plasma membrane.

• Farnesyltransferase inhibitors (FTIs) (e.g., tipifarnib):

  • Work well for HRAS-mutant tumors (since HRAS cannot use alternative geranylgeranylation).

  • Less effective for KRAS/NRAS (bypass via alternative prenylation).

(B) Block upstream activation

• SOS inhibitors (e.g., BI-1701963): prevent RAS activation by GEFs.

• SHP2 inhibitors (e.g., TNO155, RMC-4630): SHP2 links RTKs → RAS activation. Inhibition blunts growth factor–driven RAS signaling.

4. Targeting Downstream Pathways

(A) RAF inhibitors

• First-generation (vemurafenib, dabrafenib) work only in BRAF V600E melanoma (not KRAS/NRAS).

• Paradoxical activation in RAS-mutant cancers due to RAF dimerization.

(B) MEK inhibitors

• Trametinib, Cobimetinib, Selumetinib.

• Reduce ERK activation → partial efficacy in RAS-driven tumors.

• Resistance and toxicity limit use as single agents.

(C) ERK inhibitors

• Target the final node (ERK1/2).

• Drugs in development: Ulixertinib (BVD-523).

• Resistance: ERK reactivation via feedback.

(D) PI3K–AKT–mTOR inhibitors

• Since RAS also activates PI3K, dual blockade may help.

• Agents: PI3K inhibitors (alpelisib), AKT inhibitors (capivasertib), mTOR inhibitors (everolimus).

• Often need combinations with MAPK inhibitors.

5. Synthetic Lethality with RAS

• Tumors addicted to RAS often become vulnerable when a partner pathway is inhibited. Examples:

  • RAS + PARP inhibition (DNA repair stress).

  • RAS + autophagy inhibition (hydroxychloroquine trials).

  • RAS + SHP2 or SOS1 inhibition (block adaptive resistance).

6. Immuno-Oncology and RAS

• RAS-driven tumors are immunosuppressive (via cytokines, PD-L1 upregulation).

• Combining KRAS inhibitors with checkpoint blockade (PD-1/PD-L1 inhibitors) is being tested.

• KRAS inhibition may enhance antigen presentation → more immunogenic tumors.

7. Current Clinical Status

• KRAS G12C inhibitors: Sotorasib & Adagrasib approved (NSCLC, colorectal trials ongoing).

• KRAS G12D inhibitors: MRTX1133 → promising preclinical, entering trials.

• SHP2 inhibitors: several in clinical trials, often in combo with KRAS inhibitors.

• HRAS inhibitors: Tipifarnib in HRAS-mutant head & neck squamous carcinoma.

✅ Summary:Inhibition of the RAS pathway can be approached in three ways:

1. Direct targeting of mutant RAS (KRAS G12C/G12D inhibitors, degraders).

2. Indirect blockade of activation (SOS, SHP2, prenylation).

3. Downstream blockade (RAF, MEK, ERK, PI3K/AKT/mTOR).

The most promising advances are mutation-specific inhibitors (KRAS G12C, KRAS G12D) and combinations with downstream or immune therapies. Resistance remains the main challenge, driving the need for multi-target strategies.