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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Erasca wants to start on a fresh page, seeking a partner for its most clinically advanced asset.\n Cancer company Erasca is seeking a partner for its most advanced asset, a pan-RAF inhibitor being studied in a phase 3 melanoma study and a phase 1b solid tumor trial, in hopes of adding another year onto its cash runway.The strategic decision to end further internal development of the ex-Novartis asset, dubbed naporafenib, will allow Erasca to focus on its two early-stage RAS-targeting candidates. The company in-licensed those prospects from two different biotechs almost exactly a year ago.The move is expected to further the biotech’s cash runway from the second half of 2027 to the second half of 2028, according to a May 13 release.The San Diego company is already in discussions related to partnership opportunities for naporafenib, according to the release.Evercore analysts called the decision \"great news\" in a May 13 note, writing that naporafenib was proving to be an overhang for Erasca. The analyst firm cited the importance of an extra year of funding amid the current macroeconomic environment, noting that the move eliminates the risk tied to seeking future funding on the back of potentially mixed or tough-to-interpret trial results.   The sidelined asset has snagged FDA fast-track designation for use with trametinib in patients with unresectable or metastatic melanoma whose tumors contain an NRAS mutation (NRASm).Erasca pointed to a pooled analysis of patients with NRASm melanoma who received the investigational combo in phase 1 and 2 trials, saying the data demonstrated a clinically meaningful extension of median progression-free survival and median overall survival when compared to historical benchmarks.The asset, which Erasca picked up from Novartis for $20 million in 2022, would be the first targeted therapy in NRASm melanoma if it were to make it to market. “Having more than three years of cash despite no new infusion of capital in this volatile macroenvironment bolsters our ability to focus on successfully executing our ambitious clinical development plans for ERAS-0015 and ERAS-4001,” Erasca CEO and cofounder Jonathan Lim, M.D., said in the release.The San Diego company just received FDA clearance to enter clinical trials for ERAS-0015, a pan-RAS molecular glue with potential for treating RAS-mutant (RASm) solid tumors. The biotech also wrapped up a submission asking for the agency’s approval to enter human studies for pan-KRAS inhibitor ERAS-4001, with phase 1 monotherapy data for both programs expected by next year.“We believe that the broad clinical application of these validated RAS targets, the robust excitement for our competitive candidates, and the tremendous progress we have made across both programs since their in-licensing last May strongly position us for success as we aim to help treat the millions of patients with RASm solid tumors,” the CEO explained. Erasca spent a collective $22.5 million to import the candidates last year, with ERAS-4001 coming from Medshine Discovery and ex-China rights for ERAS-0015 coming from Joyo Pharmatech.To make room for the new assets, Erasca last year called it quits on its internal pan-KRAS program and deprioritized two other programs. In conjunction, the company let go of 18% of its team, with most of the affected roles located in drug discovery functions or the deprioritized programs.Editor\'s note: This story was updated at 11:45 a.m. ET on May 13 to include analyst insight.