ulixertinib (BVD-523)

ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations.

ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.

Our candidate approach identifies FOXN3-AS1 as a prognostic indicator of survival in AML with a potential immune-related role. The preliminary observations we made on FOXN3-AS1/DNMT1 crosstalk warrant more in-depth invested immunotherapeutic approaches in AML.

Importantly, the BRAF/RAF1 inhibitor naporafenib, the MEK inhibitor trametinib and the ERK inhibitor ulixertinib failed to reduce pT401 levels in these settings, supporting an alternative ERK-independent pathway to T401 phosphorylation...Conversely, genetic mTOR pathway activation by oncogenic RHEB (Q64L) and mTOR (S2215Y and R2505P) mutants substantially increased pT401, an effect that was reverted by dactolisib and torin1 but not by trametinib...Using mass spectrometry, we provide further evidence that torin1 suppresses the phosphorylation of T401, S405 and S409 but not of other important regulatory phosphorylation sites such as S446, S729 and S750. In summary, our data identify the mTOR axis and its inhibitors of (pre)clinical relevance as novel modulators of BRAF phosphorylation at T401.

P1, N=27, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Mar 2026 --> Mar 2028

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Apr 2026 --> Nov 2026 | Trial primary completion date: Jul 2024 --> Aug 2025

ERK1/2 (ulixertinib and SCH772984), MEK1/2 (binimetinib), and PI3K (pictilisib) inhibitors inhibited growth of RRAS Q87L or RRAS2 Q72L cells more potently than cells expressing wildtype proteins. Oncogenic R RAS/RRAS2 mutations were detected in LUAD at a rate similar to some other well-characterized lung cancer drivers, such as HRAS/NRAS hotspot mutations or NRG1 fusions. Our study supports the inclusion of RRAS /RRAS2 into routine molecular diagnostic protocols for precision oncology and clinical development of pan-RAS inhibitors, such as RMC-6236, for patients with these driver mutations in order to fully realize the potential benefit of RAS-targeted therapies.

P2, N=47, Terminated, BioMed Valley Discoveries, Inc | N=215 --> 47 | Trial completion date: Mar 2025 --> Jul 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> May 2024; Lack of Enrollment for Remaining Open Baskets

Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

P2, N=38, Recruiting, Memorial Sloan Kettering Cancer Center

Treatment with the neural precursor cell expressed developmentally downregulated protein 8-activating enzyme inhibitor pevonedistat resulted in increased hPRLrL and the death of breast cancer cells. Treatment of breast cancer cells with ERK1/2 inhibitor ulixertinib resulted in decreased colony-forming ability and less proliferation. These studies suggest that the hPRLrI I-tail contributed to breast oncogenesis and may be a promising target for the development of new breast cancer therapies.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

This study reveals the potent antitumor activity of BVD-523 against thyroid cancer cells bearing MAPK-activating mutations, offering promise for treating aggressive forms of thyroid cancer.

ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.

P1, N=27, Recruiting, M.D. Anderson Cancer Center | Suspended --> Recruiting

P1, N=18, Completed, University of Utah | Active, not recruiting --> Completed

P2, N=101, Terminated, BioMed Valley Discoveries, Inc | Active, not recruiting --> Terminated; Enrollment challenges

P2, N=215, Recruiting, BioMed Valley Discoveries, Inc | Trial completion date: Jun 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

P1, N=27, Suspended, M.D. Anderson Cancer Center | Phase classification: P1b --> P1 | Not yet recruiting --> Suspended

Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

P2, N=20, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2024 --> Mar 2026

P1b, N=27, Not yet recruiting, M.D. Anderson Cancer Center

Our study highlights the exacerbation of lung-to-brain metastasis via miR-21-rich EV secretion. This underlines the therapeutic promise of targeting the miR-21/ERK/STAT3 pathway with ulixertinib for managing brain metastasis from lung cancer.

Our results provide a novel understanding of TAME at the single-cell level. Based on our findings, several adipocyte subtypes have negative impact on prognosis. These cancer-associated adipocytes may serve as key prognostic predictor and potential targets for treatment in the future.

P2, N=20, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2023 --> Apr 2024

P1, N=20, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Sep 2023 --> Apr 2023

P1, N=20, Not yet recruiting, M.D. Anderson Cancer Center

KRASG12C mutant-inhibitors, including AMG-510 (sotorasib), MRTX849 (adagrasib), and JDQ443 have demonstrated efficacy in KRASG12C-mutant cancers, including NSCLC. Expression of the mutant KRAS alleles were readily confirmed from RNA sequencing data in all models. Gene expression analysis showed differential expression of MAPK pathway genes in monotherapy versus combination therapy treated groups.In summary, ulixertinib combined with adagrasib exhibited robust pre-clinical activity in a variety of xenograft models with KRASG12C and should be further evaluated.

BRAF plus EGFR inhibition (encorafenib with cetuximab) is an FDA approved treatment option for adult patients with metastatic CRC...The addition of a MEK inhibitor, binimetinib, did not confer overall survival benefit...The patient was treated under the Expanded Access Protocol (NCT04566393) for compassionate use access to ulixertinib. Preclinical data and clinical complete response warrants further investigation of ulixertinib plus BRAF and EGFR inhibition.

In live imaging experiments, we found that blocking ERK activity with the ERK inhibitor Ulixertinib blocks the induction of cell death after IFNg treatment in 17 of 23 (~74%) IFNg-sensitive PDM lines covering all the MAPK mutant and triple wildtype molecular subtypes of melanoma...This pathway is active in all melanoma subtypes, making it an attractive target to enhance IFNg GI in tumor cells. Our results provide a new understanding of the IFNg GI pathway that will also be crucial to define mechanisms of GI resistance in tumor cells.

P1, N=18, Active, not recruiting, University of Utah | Recruiting --> Active, not recruiting | N=12 --> 18

SARS-CoV-2-correlated ASGR1 is a novel marker that can be used for treating and identifying multiple human cancers.

P2, N=6452, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=101, Active, not recruiting, BioMed Valley Discoveries, Inc | Recruiting --> Active, not recruiting | N=528 --> 101

Additionally, ulixertinib treatment significantly sensitized NB cells to the conventional chemotherapeutic agent doxorubicin. Furthermore, ulixertinib potently inhibited NB tumor growth and prolonged the overall survival of the treated mice in two different NB mice models. Our preclinical study demonstrates that ulixertinib, either as a single agent or in combination with current therapies, is a novel and practical therapeutic approach for NB.

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Active, not recruiting --> Recruiting

P1, N=45, Active, not recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Oct 2023 --> Apr 2026 | Trial primary completion date: Oct 2022 --> Jul 2024

Based on these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). Additionally, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to PDAC patients.

The clinically available MAPK inhibitor Ulixertinib showed enhanced toxicity in FLCN cells...Also, we identified that FLCN inactivation resulted in dephosphorylation of TFEB Ser109, Ser114, and Ser122, which may be linked to increased oxidative stress levels in FLCN cells. Together, our study highlights differential phosphorylation of specific kinases and substrates in FLCN renal cells. This provides insight into BHD-associated renal tumorigenesis and may point to several novel candidates for targeted therapies.