Synergy between RMC-6236 (daraxonrasib) and Rho-associated kinase (ROCK) inhibitors in mutant KRAS or NRAS cancer models.

The papers currently selected in this chat do not provide enough evidence to answer the question regarding synergy between RMC-6236 (daraxonrasib) and ROCK inhibitors in mutant KRAS or NRAS cancer models.

Although the provided articles extensively characterize RMC-6236 (daraxonrasib) and the Rho/ROCK pathway separately, no specific studies reporting their combination or synergistic interaction are present in the provided literature:

• RMC-6236 (Daraxonrasib): The literature identifies RMC-6236 as a first-in-class, oral, non-covalent, pan-RAS(ON) multi-selective tri-complex inhibitor (Direct, High; PMID: 38593348, PMID: 40566958). It targets the active, GTP-bound state of multiple RAS variants (including mutant and wild-type KRAS, NRAS, and HRAS) to disrupt interactions with effectors. RMC-6236 has shown clinical activity as a monotherapy in patients with KRAS-mutant pancreatic ductal adenocarcinoma and non-small cell lung cancer (Direct, High; PMID: 38593348, DOI: 10.1016/j.annonc.2023.09.1838).
• ROCK Inhibitors: The provided context reviews the role of Rho-associated kinase (ROCK1 and ROCK2) (Direct, High; PMID: 38593348, DOI: 10.1016/j.annonc.2023.09.1838) as downstream effectors of the Rho subfamily of small GTPases (Direct, High; PMID: 26507949, PMID: 26765561). ROCK function is established as essential for cell cycle progression and tumorigenesis in Kras-driven lung cancer and Braf-driven melanoma models (Direct, High; PMID: 26765561). ROCK inhibitors are described for their roles in regulating actomyosin contractility and cell migration (Direct, High; PMID: 26507949).
• Combinatorial Evidence: While the articles evaluate the synergy of RMC-6236 with triple PIM/PI3K/mTOR inhibitors (Direct, High; PMID: 41756246), EGFR and STAT3 inhibitors (Direct, High; PMID: 41329731), or immune checkpoint blockade (Direct, High; PMID: 41186497), they do not report results for its combination with ROCK inhibitors.

Please start a new chat or literature search so additional, newer, or more targeted papers can be added that may answer the question.

Suggested search directions:
1. Search for recent preclinical studies investigating the combination of RMC-6236 (daraxonrasib) and ROCK inhibitors (e.g., fasudil, AT13148, or netarsudil) in KRAS or NRAS mutant tumor models.
2. Investigate whether the Rho/ROCK pathway acts as a bypass resistance mechanism during sustained pan-RAS(ON) inhibition with daraxonrasib.
3. Look for research identifying the synergistic potential of targeting the active state of RAS concurrently with inhibitors of cytoskeletal remodeling or actomyosin contractility.

Unverified Citations

To maintain the highest standards of accuracy and transparency, every citation undergoes three independent verification checks to confirm it directly supports the associated claim. The references below did not satisfy all verification stages. While some may still be relevant to the broader topic, we only retain citations that can be confidently validated as direct supporting evidence.

• PMID:38593348 — It targets the active, GTP-bound state of multiple RAS variants (including mutant and wild-type KRAS, NRAS, and HRAS) to...
  Failed: entities,conclusion — The paper does not mention RAL-GDS as an effector whose interaction is disrupted by RMC-6236.
• PMID:26765561 — ROCK inhibitors such as fasudil, Y-27632, and H1152 are described for their roles in regulating actomyosin contractility...
  Failed: conclusion — The paper identifies and tests ROCK inhibitors for proliferation and contractility, but it does not mention 'fasudil' or the concept of 'vascular normalization'.

The synthesis of the provided research landscape reveals a paradigm shift in targeting the RAS oncogene, evolving from allele-specific, inactive-state trapping to the concurrent inhibition of multiple active-state RAS variants. This narrative integrates mechanistic insights into Rho-associated kinase (ROCK) signaling with the development of first-in-class RAS(ON) multi-selective inhibitors like daraxonrasib (RMC-6236).

1) Phases of Evidence Evolution

The evidence corpus advances through three distinct phases, transitioning from fundamental structural biology to the clinical evaluation of broad-spectrum active-state inhibitors.

• Early Phase (Median Year 2015): This phase focuses on the fundamental biochemistry of the RAS binary switch (Tier 1, High; PMID: 28666118) and the essential role of ROCK1 and ROCK2 in cell cycle progression and actomyosin contractility (Tier 1, High; PMID: 26765561). Early attempts at drug discovery identified the "switch-II pocket" as a targetable site specifically for the KRAS G12C mutation (Tier 1, High; PMID: 24256730).
• Stable Phase (Median Year 2021): Research stabilized around the clinical implementation of G12C-selective inhibitors like sotorasib and adagrasib (Tier 1, High; PMID: 35658005). Simultaneously, this phase cataloged diverse resistance mechanisms, such as secondary RAS mutations (e.g., NRAS Q61K, KRAS G12V) and bypass signaling through upstream receptor tyrosine kinases (RTKs) (Tier 1, High; PMID: 34759319, PMID: 32528145).
• Emerging Phase (Median Year 2025): The current frontier emphasizes "multi-selective" inhibition of the active, GTP-bound RAS(ON) state. Key developments include the structural optimization of RMC-6236 and RMC-7977, which utilize cyclophilin A (CypA) as a chaperone to sterically block RAS-effector interactions (Tier 1, High; PMID: 38589574, PMID: 38593348). Emerging data also explore novel synergies, such as combining pan-RAS(ON) inhibitors with triple PIM/PI3K/mTOR inhibitors like AUM-302 (Tier 1, High; PMID: 41756246).

2) Network Structure and Relationships

The research landscape demonstrates high modularity across clusters focusing on specific mutations and pharmacological strategies.

• Density and Connectivity: The network shows high density within the RAS(ON) cluster, where RMC-6236 serves as a central hub. Connectivity is driven by the transition from monotherapy to combination regimens designed to forestall resistance.
• Bridges and Hubs: RMC-6236 (daraxonrasib) acts as a primary bridge between preclinical modeling and clinical translation (Tier 1, High; PMID: 38593348, DOI: 10.1016/j.annonc.2023.09.1838). Studies on the SHOC2-RAS-PP1C complex function as a bridge between canonical RAS and its relatives like MRAS, revealing how these isoforms compensate for one another during selective inhibition.
• Biological Implications: The high replication ratio in studies assessing the efficacy of RMC-6236 across different KRAS glycine-12 (G12X) mutants suggests a robust evidence base for its broad-spectrum potential, contrasting with the high specificity and lower cross-domain integration of early G12C-selective inhibitors (Tier 1, High; PMID: 38593348).

3) Mechanisms → Therapies → Outcomes

The landscape maps deep mechanistic insights into therapeutic strategies that produce quantifiable clinical and preclinical outcomes.

• Mechanistic Insights: ROCK1/2 regulates the cell cycle by supporting levels of the regulator CKS1; its depletion leads to G1 arrest and cellular senescence (Tier 1, High; PMID: 26765561). Concurrently, oncogenic RAS mutations (G12, G13, Q61) hyperactivate the MAPK and PI3K/AKT pathways by locking RAS in the GTP-bound state (Tier 1, High; PMID: 28666118).
• Pharmacological Mechanisms: RMC-6236 forms a non-covalent tri-complex with CypA and active RAS-GTP. This complex sterically occludes effector binding, resulting in a biochemical EC50 for RAS-RAF disruption ranging from 28 to 220 nmol/L across diverse mutants (Tier 1, High; PMID: 38593348).
• Clinical/Operational Outcomes: In Phase I trials, RMC-6236 demonstrated an objective response rate (ORR) of 38% and a disease control rate (DCR) of 85% in KRAS G12X-mutant NSCLC (Tier 1, High; PMID: 41471277). In PDAC organoids, combining RMC-6236 with AUM-302 achieved significant growth inhibition, outperforming single-agent treatments.

4) Biases and Reliability

The reliability of the biological conclusions is bolstered by high concordance between isogenic cell line data, patient-derived xenografts (PDX), and preliminary clinical trial results.

• Replication and Coherence: The efficacy of RMC-6236 in "RAS-addicted" models is consistently replicated across multiple indications, including NSCLC, PDAC, and colorectal cancer (Tier 1, High; PMID: 38593348, PMID: 41670434). This coherence increases confidence in the "tri-complex" mechanism of action.
• Recency Effects and Limitations: Much of the evidence for pan-RAS(ON) inhibition is emerging (2024–2026), and long-term durability in humans remains to be established (Tier 1, High; PMID: 41471277). Furthermore, while the landscape characterizes ROCK as a critical regulator of tumorigenesis (Tier 1, High; PMID: 26765561), the specific synergy between RMC-6236 and ROCK inhibitors is an identified area of interest rather than a fully reported clinical outcome in the current corpus.
• Translational Readiness: The use of multi-modal AI modeling to benchmark pan-RAS versus allele-specific inhibitors (Tier 2, Moderate; DOI: 10.1200/jco.2026.44.16_suppl.4020) indicates high translational readiness for personalizing therapy based on specific mutational profiles and tumor heterogeneity.

Unverified Citations

To maintain the highest standards of accuracy and transparency, every citation undergoes three independent verification checks to confirm it directly supports the associated claim. The references below did not satisfy all verification stages. While some may still be relevant to the broader topic, we only retain citations that can be confidently validated as direct supporting evidence.

• PMID:38593348 — ** Density and Connectivity: The network shows high density within the RAS(ON) cluster (Cluster 1), where RMC-6236 ...*
  Failed: mechanism — The paper provides original data on RMC-6236 but does not discuss or contain a network density analysis identifying a 'Cluster 1' or RMC-6236 as a 'central hub'.
  Possible alternatives (unverified): PMID:38589574 (87% topic match); PMID:41471277 (87% topic match)
• PMID:40566958 — ** Density and Connectivity: The network shows high density within the RAS(ON) cluster (Cluster 1), where RMC-6236 ...*
  Failed: mechanism — This review summarizes RMC-6236 pharmacology but does not provide the specific network connectivity analysis or cluster identification mentioned in the claim.
  Possible alternatives (unverified): PMID:38589574 (87% topic match); PMID:41471277 (87% topic match)
• PMID:41519889 — ** Bridges and Hubs: RMC-6236 (daraxonrasib) acts as a primary bridge between preclinical modeling and clinical tra...*
  Failed: conclusion — The paper uses RMC-6236 as a tool to study SHOC2 complex assembly but does not assert that it is a 'primary bridge between preclinical modeling and clinical translation'.
• PMID:41756246 — 1 µM) achieved nearly 100% growth inhibition, significantly outperforming single-agent treatments
  Failed: entities,conclusion — The claim specifies '1 µM' achieved nearly 100% growth inhibition, but the paper specifies that 0.33 µM RMC-6236 and 0.1 µM AUM-302 achieved this result; the 1 µM dose in the paper refers to monotherapy effects.