ClpP Agonism and RAS Inhibitor Resistance

A differentiated combination strategy for RAS-driven cancers

RAS inhibitors have established that mutant RAS can be therapeutically targeted. However, the clinical data also show a central limitation: many patients with the correct RAS mutation for the drug being used do not achieve a deep response, and responding tumors often rapidly develop resistance.

In KRAS G12C-mutant non-small cell lung cancer, approved KRAS G12C inhibitors have produced objective response rates of approximately 37–43%. These are important clinical results, but they also mean that more than half of treated patients do not achieve RECIST-defined objective tumor shrinkage. In KRAS G12C-mutant colorectal cancer, single-agent response rates have been substantially lower, highlighting the importance of intrinsic resistance and the need for combination therapy.

The importance of RAS inhibition has now been further underscored in pancreatic cancer. In the Phase 3 RASolute 302 trial, daraxonrasib, an oral RAS(ON) multi-selective inhibitor, doubled median overall survival in previously treated metastatic pancreatic ductal adenocarcinoma compared with chemotherapy. Median overall survival was 13.2 months with daraxonrasib versus 6.6 months with chemotherapy in the RAS G12 population, with a 60% reduction in the risk of death. These landmark data validate RAS inhibition as a major therapeutic advance in pancreatic cancer, while also reinforcing the need for rational combination strategies that can deepen and extend responses.

As a result, RAS drug development is rapidly moving toward rational combinations. The central question is no longer simply whether RAS can be inhibited. The question is how responses can be made deeper, broader, and more durable.

This creates a clear rationale for evaluating ClpP agonists as RAS inhibitor combination partners, particularly in RAS-driven tumors with intrinsic, adaptive, or acquired resistance.

 

Why pathway-focused combinations may not be enough

Many current RAS inhibitor combination strategies are designed to further suppress RAS/MAPK pathway signaling. These include combinations with EGFR, SHP2, SOS1, MEK, ERK, PI3K-pathway agents, RTK-directed therapies, chemotherapy, and immune-directed therapies.

These approaches are rational, but many remain closely tied to RAS-pathway signaling or adjacent escape pathways. That is an important limitation because resistance to RAS inhibition is not one mechanism. It is many mechanisms.

Clinical and translational studies have identified a broad range of resistance mechanisms, including secondary RAS alterations, KRAS amplification, upstream receptor tyrosine kinase activation, MET amplification, MAPK-pathway mutations, gene fusions, bypass signaling, tumor suppressor loss, altered cell state, lineage plasticity, metabolic adaptation, and survival of residual tumor-cell populations.

This diversity matters. If a tumor can escape RAS inhibition through multiple genetic and non-genetic routes, then simply adding another pathway inhibitor may not fully address the biology of residual disease or acquired resistance. Deeper pathway suppression may be more effective in specific tumor settings, but it may not eliminate stressed, adapting, or metabolically rewired cancer cells that survive RAS-pathway blockade.

 

TR-107: a ClpP agonist combination strategy for RAS inhibitor resistance

Madera’s approach is different.

TR-107 is not designed to add another layer of RAS-pathway inhibition. It is a next-generation ClpP agonist designed to activate mitochondrial ClpP and disrupt mitochondrial protein homeostasis. The goal is to target a different survival axis: mitochondrial and proteostatic vulnerabilities that may persist — or become more important — when RAS-driven tumor cells are placed under therapeutic stress.

This approach also leverages TR-107’s compelling single-agent efficacy in multiple RAS-driven cancer cell lines, supporting its evaluation as both a single-agent oncology therapy and a rational combination partner.

In this context, TR-107 represents a mechanistically distinct combination concept:

RAS inhibitors suppress oncogenic signaling. TR-107 appears to exploit mitochondrial and proteostatic vulnerabilities in residual or adapting tumor cells that survive RAS-pathway inhibition.

 

Der group findings support the ClpP/RAS-resistance hypothesis

Recent work from the Channing Der group and collaborators directly supports evaluation of ClpP agonists in KRAS-mutant pancreatic cancer and RAS inhibitor resistance.

The study evaluated Modeyso® (dordaviprone; formerly ONC201), the first FDA-approved ClpP agonist/protease activator, in KRAS-mutant pancreatic ductal adenocarcinoma models, with TR-107 extending these findings to Madera’s highly potent and specific next-generation ClpP agonist. Modeyso/dordaviprone suppressed PDAC cell growth, required ClpP expression for activity, disrupted mitochondrial respiration, and showed additive activity with the RAS(ON) multi-selective inhibitor RMC-7977.

Importantly, ClpP activation retained activity in models with acquired resistance to RMC-7977 and in KEAP1-loss resistance models. These findings connect ClpP activation to one of the most important challenges in the RAS field: tumors that fail to respond adequately to RAS inhibition or become resistant over time.

The inclusion of TR-107 is important because it extends the ClpP/RAS-resistance findings beyond Modeyso/dordaviprone to Madera’s more potent, next-generation ClpP agonist, supporting evaluation of TR-107 in RAS-driven tumors and RAS inhibitor resistance translational models.

 

TR-107 is a next-generation ClpP agonist

Modeyso/dordaviprone provides clinical validation that pharmacologic ClpP activation can produce therapeutic benefit in a historically refractory cancer. It is the first FDA-approved systemic therapy for H3 K27M-mutant diffuse midline glioma, including DIPG — a disease setting in which more than 200 prior clinical trials with other approaches failed to produce an approved drug.

This clinical experience is also important for another reason. Mitochondrial-targeting cancer agents have often raised concerns about toxicity. Modeyso/dordaviprone provides a clinically meaningful counterexample: in the FDA safety population of 376 adult and pediatric glioma patients, permanent discontinuation due to an adverse reaction occurred in 2.1% of patients, dosage interruptions occurred in 6%, and dose reductions occurred in 2.7%. The most common adverse reactions were fatigue, headache, vomiting, nausea, and musculoskeletal pain, while the most common Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased calcium, and increased alanine aminotransferase.

However, Modeyso/dordaviprone is a first-generation ClpP agonist that displays micromolar activity in various cancer cell lines.

TR-107 is Madera’s next-generation ClpP agonist. Compared with ONC201/Modeyso, TR-107 is highly specific for ClpP and has demonstrated greater than 100-fold increased potency in multiple cancer models. TR-107 was designed to more directly exploit ClpP biology as both a single-agent oncology therapy and a rational combination partner.

For RAS-driven cancers, the development hypothesis is clear:

RAS inhibition creates therapeutic stress. TR-107 may exploit mitochondrial and proteostatic vulnerabilities that remain or increase under that stress.

Madera is evaluating TR-107 as a mechanistically distinct approach to RAS inhibitor combinations, residual disease, and RAS inhibitor resistance, with particular relevance to KRAS-mutant pancreatic cancer and potential broader relevance across RAS-driven tumors.