Naporafenib

Researchers in Canada report preclinical evidence that type II RAF inhibition may overcome both innate and acquired resistance to MAPK inhibitors in anaplastic thyroid cancer, a disease where responses to current BRAF-targeted therapy are often short-lived. The study findings were published May 18, 2026 in Cell Reports Medicine. The work was carried out by teams at at Western University and London Health Sciences Centre in London, Ontario, Canada, working with collaborators at the Ontario Institute for Cancer Research. Anaplastic thyroid cancer remains one of the most lethal human malignancies, with few effective systemic options and a median survival measured in months. The MAPK pathway, hyperactivated in the majority of ATC cases through mutations including BRAF V600E, has been a primary therapeutic target, but durable responses to existing inhibitors have remained elusive. Even patients with BRAF V600E-driven tumors frequently fail to sustain benefit from the type I RAF inhibitor dabrafenib, which is approved in combination with trametinib for BRAF V600E-mutant ATC. The study from Anthony C. Nichols and colleagues addresses a core question in the field: why do these tumors resist MAPK pathway inhibition, and what alternative pharmacological strategy might circumvent that resistance. The research team used a multi-platform approach anchored in a single index patient whose BRAF V600E ATC was profiled across five spatially distinct pre-treatment tumor regions and one post-treatment sample. This multi-region whole-genome sequencing strategy was designed to capture intratumoral heterogeneity and clonal evolution under therapeutic pressure. Complementary technologies included whole-exome sequencing, single-nucleus RNA sequencing of 6,367 high-quality cells, reverse-phase protein arrays for phosphoproteomic profiling, and patient-derived xenograft models built from two separate BRAF V600E ATC patients. EphA2 as a tissue-specific driver of RAF inhibitor resistance A central mechanistic finding of the study is the identification of EphA2, a receptor tyrosine kinase, as a tissue-specific mediator of RAF inhibitor resistance in thyroid cancer. EphA2 phosphorylation at serine 897 was found to be substantially elevated in thyroid cancers relative to melanoma and colorectal cancer, two tumor types where type I RAF inhibitors have established clinical utility. Because EphA2 activates both the MAPK and PI3K-AKT signaling axes simultaneously, its elevated activity in thyroid tissue creates a dual bypass mechanism that allows tumor cells to maintain downstream signaling even when BRAF is pharmacologically inhibited. RAF inhibitors that perform well in BRAF V600E melanoma show considerably less durable activity in thyroid cancer. The study’s phosphoproteomic data indicated that naporafenib, a type II RAF inhibitor, reduced EphA2 serine 897 phosphorylation by approximately sevenfold, an effect not observed with dabrafenib. Because naporafenib targets the inactive DFG-out conformation of RAF, it inhibits both BRAF and CRAF and suppresses RAF dimer activity — the mechanism by which elevated RAS signaling, common in thyroid cancers, causes paradoxical MAPK reactivation with type I inhibitors. Across a panel of nine thyroid cancer cell lines, naporafenib demonstrated lower IC50 values than dabrafenib in BRAF V600E lines and maintained activity in lines with elevated RAS signaling, where dabrafenib caused paradoxical pathway activation. Naporafenib-trametinib efficacy in PDX models In vivo validation was conducted in two patient-derived xenograft models. In the primary PDX derived from the index patient, naporafenib monotherapy produced statistically significant tumor growth inhibition relative to vehicle control. The combination of naporafenib and trametinib produced superior tumor regression compared to naporafenib alone, with near-complete regression observed in multiple animals. These results were replicated in a second PDX model derived from an independent BRAF V600E ATC patient, confirming that the findings were not specific to a single tumor. Treated animals tolerated the combination without significant weight loss or overt toxicity signals at efficacious doses. The combination also demonstrated activity in PDX models that had progressed on prior dabrafenib-trametinib treatment. Switching to naporafenib-trametinib induced tumor regression in these resistant models, suggesting that the mechanistic differences between type I and type II RAF inhibition are sufficient to re-sensitize tumors that have escaped the standard regimen. The study notes that acquired resistance to dabrafenib-trametinib in this setting was accompanied by MAPK pathway reactivation and expansion of CD163-positive tumor-associated macrophages, neither of which prevented naporafenib from engaging its target. Acquired resistance ATC: the MAST1 escape mechanism The study also characterized a resistance mechanism specific to naporafenib itself, providing a translational roadmap for anticipating treatment failure. Multi-region sequencing of the index patient’s post-treatment tumor identified amplification and upregulation of MAST1, a kinase component of the CRAF-MEK1 complex. Functional validation confirmed that elevated MAST1 conferred resistance to naporafenib-trametinib by reactivating MAPK signaling through CRAF-independent phosphorylation of MEK1. A specific MAST1 variant, Ala733Val, expanded from less than 0.2% variant allele frequency at baseline to 47% at the point of naporafenib resistance in the syngeneic mouse model, indicating strong positive selection under drug pressure. This finding positions MAST1 as a candidate biomarker of emerging resistance and a potential cotarget for future combination strategies. The authors note that the genotype-agnostic activity of naporafenib across BRAF-mutant, RAS-mutant, and wild-type ATC cell lines is a feature of particular relevance given that approximately 50 to 80% of ATC patients lack BRAF V600E and currently have no approved targeted therapy. Translational context and remaining steps The study is entirely preclinical, and the authors state that the work rationalizes clinical investigation of type II RAF inhibitors in thyroid cancer rather than establishing clinical benefit. Naporafenib is currently in clinical development by Novartis for other indications, and its tolerability profile in humans has been characterized in earlier-phase studies, though no ATC-specific clinical trial data are reported in this paper. The identification of MAST1 as an acquired resistance mechanism to naporafenib-trametinib suggests that prospective clinical studies in ATC would benefit from serial genomic monitoring and potentially from upfront combination strategies targeting MAST1. The research was funded by the Canadian Institutes of Health Research, Genome Canada, the Ontario Genomics Institute, and the Ontario Institute for Cancer Research. Meta description: Western University study identifies naporafenib-trametinib as a strategy to overcome innate and acquired MAPK inhibitor resistance in anaplastic thyroid cancer preclinically. 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A clinical-stage combination strategy for RAS-mutant solid tumors moves forward as Erasca (Nasdaq: ERAS), a San Diego-based precision oncology company, announced a clinical trial collaboration and supply agreement with Merck to evaluate ERAS-0015 in combination with Keytruda (pembrolizumab) in patients with RAS-mutant solid tumors. The agreement is a clinical trial collaboration and supply agreement, a structure under which Erasca sponsors and operationally manages the AURORAS-1 Phase I study while Merck supplies pembrolizumab at no cost. Each company retains independent rights to its respective asset; the collaboration does not grant either party commercialization rights over the other’s compound. Erasca is sponsoring the study, bearing the financial and regulatory responsibilities of trial execution. Merck’s contribution is limited to drug supply, reflecting a conventional CTCSA structure in which a large pharma partner enables combination evaluation without taking on broader development obligations. ERAS-0015 asset profile and scientific rationale ERAS-0015 is an investigational oral pan-RAS molecular glue designed to inhibit RAS signaling across multiple RAS mutant variants, including wildtype RAS. The compound is currently being evaluated in the AURORAS-1 Phase I trial (NCT06983743) in patients with RAS-mutant advanced or metastatic solid tumors. Erasca licensed full global rights to the molecule from China-based Joyo Pharmatech Co., Ltd in a March 2026 deal. Early dose escalation data from AURORAS-1 showed favorable safety and tolerability, linear pharmacokinetics, and confirmed and unconfirmed partial responses across multiple tumor types harboring different RAS mutations, including responses observed at doses as low as 8 mg once daily. The compound is also designed to inhibit wildtype RAS variants, a property Erasca states may help prevent resistance to mutant-selective inhibitors. The scientific rationale for the pembrolizumab combination therapy rests on the observation that RAS mutations can contribute to an immunosuppressive tumor microenvironment. Erasca’s position is that pan-RAS pathway inhibition with ERAS-0015 may reduce that immunosuppression and thereby complement PD-1 blockade, potentially producing more durable tumor responses. This rationale is company-stated and has not yet been tested in a controlled clinical setting; the AURORAS-1 combination arm represents the first clinical test of this hypothesis. Pembrolizumab is an approved anti-PD-1 therapy with an established profile across multiple tumor types. Its inclusion as the immunotherapy backbone in this study reflects the broader oncology field’s interest in pairing targeted pathway inhibitors with checkpoint blockade, particularly in indications where single-agent responses remain limited. Approximately 2.7 million patients are diagnosed annually with RAS-mutant tumors worldwide, according to Erasca. The absence of broadly effective pan-RAS targeting agents and the emergence of resistance mechanisms in existing RAS-directed therapies have left a substantial unmet need across this patient population. The Keytruda ERAS-0015 collaboration follows a consistent pattern of CTCSA dealmaking by Erasca. The company has pursued supply-based combination study agreements with multiple large pharma partners across its RAS/MAPK-focused pipeline. In February 2024, Erasca entered two CTCSAs with Novartis to secure supply of trametinib for the SEACRAFT-1 Phase Ib and SEACRAFT-2 Phase III studies, evaluating the pan-RAF inhibitor naporafenib in combination across RAS-mutant solid tumors and NRAS-mutant melanoma. That same partnership extended in May 2024 when Erasca in-licensed a RAS-targeting franchise from Novartis, deepening its pipeline of RAS/MAPK pathway assets ahead of pivotal trial initiation. The Merck agreement adds a third large pharma supply relationship to Erasca’s combination development strategy, this time incorporating PD-1 blockade alongside direct RAS pathway targeting. The AURORAS-1 study design evaluates ERAS-0015 both as monotherapy and in combination arms, meaning the trial will generate parallel data streams relevant to both the single-agent profile of ERAS-0015 and the combination hypothesis. This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/ Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.