ravoxertinib (RG7842) / Roche, Pfizer - LARVOL DELTA

Targeted therapy combinations with ipatasertib in multi-cell type 3D tumor spheroid models. (PubMed, Acad Oncol) - "The combination of ipatasertib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or greater-than-additive cytotoxicity in approximately half the cell lines screened. The V600E mutation-specific BRAF inhibitor vemurafenib and the KRAS G12C selective inhibitor sotorasib in combination with ipatasertib were active in the eight BRAF V600E and four KRAS G12C mutant-containing cell lines, respectively. Vertical inhibition of the PI3K/AKT/mTOR pathway with the mTORC1/2 kinase inhibitor sapanisertib demonstrated additive and/or greater-than-additive effects in multiple cell lines. In early experiments, there was a correlation between the response to ipatasertib and selumetinib in two patient-derived tumor lines grown as mct-spheroids and the corresponding patient-derived xenografts. All data are accessible via the PubChem BioAssay public database."

Journal • Oncology • KRAS

Molecular Dissection of the AHR-AREG driven EGFR-ERK1/2-CyclinD1 axis in acquired lenvatinib resistance of Hepatocellular carcinoma. (PubMed, Biochem Pharmacol) - "Furthermore, we demonstrated that targeting ERK1/2 with ravoxertinib (an ERK1/2 inhibitor) could significantly enhance the sensitivity of resistant HCC cells to lenvatinib therapy. Overall, lenvatinib-induced AHR activation promotes AREG expression, which subsequently facilitates the acquisition of drug resistance in HCC via the EGFR-ERK1/2-CyclinD1 signaling axis. Targeting ERK1/2 and AHR effectively improved the response to lenvatinib treatment in resistant HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • AREG • CCND1 • EGFR

Identification of different lung adenocarcinoma subtypes in combination with antidiuretic hormone-related genes and creation of an associated index to predict prognosis and guide immunotherapy. (PubMed, Comput Biol Chem) - "This study provided potential prognostic biomarkers for LUAD and might facilitate the development of effective immunotherapy strategies for LUAD patients."

IO biomarker • Journal • Tumor mutational burden • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DKK1 • IGFBP1 • TMB

Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids. (PubMed, SLAS Discov) - "Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib."

Journal • Oncology • KRAS

Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDH1 • CDH2 • MMP7 • SNAI1 • SNAI2 • TGM2

Enhanced suppression of the MAPK signaling pathway by ERK inhibitor combinations (ADO 2024) - "In conclusion our results show that the ERK inhibitor ravoxertinib (GDC0994) shows in single treatment only limited antitumor activity. The combination of ERKi and BRAFi/MEKi causes growth inhibition and apoptosis in BRAF mutated melanoma cells irrespective of the sensitivity to BRAF or MEK inhibitors. Additional ERKi is effective especially in a chronic, long-term setting."

Melanoma • Oncology • Solid Tumor

AIBP promotes cell proliferation and migration through the ERK1/2-MAPK signaling pathway in hepatocellular carcinoma. (PubMed, Transl Cancer Res) - "Finally, we discovered that AIBP could control the MAPK signaling pathway-involved genes expression, including P-MEK, MEK, c-Myc, P-ERK1/2, and ERK1/2, and that GDC-0994, a specific ERK1/2 inhibitor, could suppress the AIBP overexpression induced cell migration and proliferation abilities. These findings demonstrated that the ERK/MAPK signaling pathway might be stimulated by AIBP in HCC tissues, leading to increased cell invasion, migration, and proliferation. It was hypothesized that AIBP might act as a useful prognostic and diagnostic marker for HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • APOA1 • MYC

Focal cortical dysplasia II caused by brain somatic mutation of IRS-1 is associated with ERK signaling pathway activation. (PubMed, Cereb Cortex) - "Notably, the ERK inhibitor GDC-0994, rather than the mTOR inhibitor rapamycin, effectively rescued the neuronal defects. This study directly highlighted the ERK signaling pathway's role in the pathogenesis of focal cortical dysplasia II and provided a new therapeutic target for cases of focal cortical dysplasia II that are not treatable by rapamycin analogs."

Journal • CNS Disorders • Epilepsy • IRS1

The ERK inhibitor GDC-0994 selectively inhibits growth of BRAF mutant cancer cells. (PubMed, Transl Oncol) - "Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment."

Journal • Oncology • BRAF

Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2. (PubMed, Chem Res Toxicol) - "Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP...The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens."

Journal • Cholestasis • Hepatology • Liver Failure • CYP8B1 • ER • NR1H4

Elevating MAPK Pathway Suppression with Combinatorial ERK Inhibitors (EADO 2024) - "Methods The ERK1/2 inhibitor (ERKi) ravoxertinib (GDC0994) was tested in monolayer culture on different melanoma cell lines with/without an acquired resistance to either BRAF inhibitor (BRAFi) monotherapy or its combination with a MEK inhibitor (BRAFi + MEKi)...Additional ERKi is effective especially in a chronic, long-term setting. Combinatorial treatment regimens including ERK1/2 inhibitors might be an attractive, novel therapeutic strategy in BRAF mutated melanoma cells."

Melanoma • Oncology • Solid Tumor

Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis. (PubMed, Pharmacol Res) - "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."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • KRAS

Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2. (PubMed, ACS Omega) - "Immunofluorescence analysis showed that RAH attenuated neuronal apoptosis but not neuronal necroptosis in the basal cortex at 72 h after SAH in rats. Altogether, our results suggest that RAH improves long-term neurologic deficits through early inhibition of Erk1/2 in experimental SAH."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology • CASP3 • RIPK1

A proteomic signature and potential pharmacological opportunities in the adaptive resistance to MEK and PI3K kinase inhibition in pancreatic cancer cells. (PubMed, Proteomics) - "Notably, several proteins have previously been observed in pancreatic cancer cells with intrinsic resistance to the combined kinase inhibition treatment, suggesting a proteomic signature. We also found that resistant cells are sensitive to small molecule drugs ERK inhibitor GDC-0994, S6K1 inhibitor DG2 and statins."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CAV1 • KRAS

A Phase Ib study to evaluate the MEK inhibitor cobimetinib in combination with the ERK1/2 inhibitor GDC-0994 in patients with advanced solid tumors (AACR 2017) - "The safety profile of this combination of a MEK and ERK inhibition demonstrated classic MAPK-inhibitor related AEs. No new safety signals were identified. However, overlapping Grade 1-2 AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination."

Clinical • P1 data • Acute Coronary Syndrome • Biosimilar • Cardiovascular • Dermatitis • Gastrointestinal Cancer • Immunology • Oncology • Ophthalmology • Pancreatic Cancer

Erk1/2-Dependent HNSCC Cell Susceptibility to Erastin-Induced Ferroptosis. (PubMed, Cells) - "The ravoxertinib-dependent inhibition of Erk1/2 signaling led to the decrease in erastin efficacy due to the effect on ROS production and the upregulation of ROS scavengers SOD1 and SOD2, resulting in repressed lipid peroxidation. Therefore, it was concluded that the erastin-dependent activation of ferroptosis seems to be a promising approach which can be further developed as an additional strategy for the treatment of HNSCC. As ferroptosis induction via erastin is strongly dependent on the expression of Erk1/2, this MAP kinase can be considered as a predictor for cancer cells' response to erastin."

Journal • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AVEN • SLC7A11 • SOD2

ERK inhibitor: A candidate enhancing therapeutic effects of conventional chemo-radiotherapy in esophageal squamous cell carcinoma. (PubMed, Cancer Lett) - "To assess the effects of ERK-targeted therapy (GDC0994) on ESCC cells, in vitro studies including CCK-8 assay, colony formation assay, and scratch wound healing assay were conducted. Furthermore, blocking the mitogen-activated protein kinase (MAPK/ERK) pathway enhanced the therapeutic efficacy of both cisplatin and radiotherapy (p < 0.05). These findings imply the role of p-ERK in the prognosis of ESCC patients and the therapeutic value of ERK inhibitors in ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • Squamous Cell Carcinoma

Abemaciclib drug combination screening with other targeted therapies in complex multicellular tumor spheroids (AACR-NCI-EORTC 2022) - "The combination of abemaciclib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or synergistic cell killing in several of the cell lines screened. The KRAS G12C selective inhibitor sotorasib in combination with abemaciclib was active in the two KRAS G12C variant containing cell lines. The most effective combination for abemaciclib was with the CDK2/7/9 inhibitor BMS-387032, which achieved greater than one log of cytotoxicity in the majority of the complex spheroid models...HHSN261201500003I. No"

Oncology • KRAS

Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib. (PubMed, JCI Insight) - "Treatment with ravoxertinib, a pharmacological inhibitor of MAPK, reverses nuclear-to-cytoplasmic localization of Nfatc1, basement membrane development defects, lymphangiectasia, and chyle accumulation, ultimately improving survival of endothelial KRAS mutant neonatal mice. These results reveal defective lymphatic basement membrane assembly and composition as major causes of thoracic lymphangiectasia and provide a potential treatment."

Journal • Cardiovascular • Respiratory Diseases • KRAS • NFATC1

Hsa_circ_0044301 Regulates Gastric Cancer Cell's Proliferation, Migration, and Invasion by Modulating the Hsa-miR-188-5p/DAXX Axis and MAPK Pathway. (PubMed, Cancers (Basel)) - "Next, in vitro characterization and functional analysis of circRNA-0044301 was done by various assays using RNase R, actinomycin D, and RNA fluorescence in situ hybridization, as well as investigations into its use as a drug to treat tumors in a subcutaneous tumorigenesis model...Finally, we investigated the relationship between circRNA-0044301 and ravoxertinib (GDC-0994) and 5-fluorouracil (5-FU) using qRT-PCR, Western blotting, and CCK8 assays...On the mechanism, it acted as a sponge of miRNA-188-5p, could regulate the downstream target DAXX, and modulated the effect of GDC-0994 on ERK1/2 and 5-FU in cells. CircRNA-0044301/miRNA-188-5p/DAXX (ERK1/2) may be a key axis in GC progression, and circRNA-0044301 has immense potential to be a therapeutic target for GC."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • DAXX

Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors. (PubMed, J Biol Chem) - "Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRAS), colon cancer (HCT-116; KRAS), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Lung Cancer • Neuroblastoma • Oncology • Solid Tumor • KRAS • NRAS

Drug combination screening of Ipatasertib and Abemaciclib with other targeted agents in complex multicellular tumor spheroids from the NCI-60 and the National Cancer Institute’s Patient-Derived Models Repository (AACR 2022) - "For example, the combination of ipatasertib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or synergistic cytotoxicity in over half the complex spheroid models screened. The V600E variant-specific BRAF inhibitor vemurafenib and the KRAS G12C selective inhibitor sotorasib in combination with ipatasertib showed activity in the one BRAF V600E and two KRAS G12C variant containing complex spheroid models, respectively. Another effective ipatasertib combination was vertical inhibition of the PI3K/AKT/mTOR pathway with the mTORC1/2 kinase inhibitor sapanisertib, which demonstrated additive and/or synergistic responses across multiple complex spheroid models. For abemaciclib, the most successful combination was with the CDK2/7/9 inhibitor BMS-387032, which achieved greater than one log of cytotoxicity in the majority of the complex spheroid models...This project was funded in part with federal funds from the NCI, NIH, under contract..."

Clinical • Oncology • KRAS

Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation (AACR 2022) - "CC-91516 (also called CC0776314), a selective and potent inhibitor of ERK1/2 and NLK, was discovered via a phenotypic screen of a kinase-focused library for compounds that synergize with mTOR kinase inhibitor CC-223 to induce apoptosis in combination with CC-223...Crystal structure of CC-91516 in complex with ERK2 reveals that its 2, 4, 6-trichlorophenyl moiety binds to a unique back pocket of the adenosine-5′-triphosphate (ATP) binding site of ERK2, which is not accessible to other ERK inhibitors such as BVD-523 and GDC-0994...In addition, CC-91516 potently induces apoptosis, inhibits survival, and overcomes resistance to MEK inhibitor trametinib of BRAF or CTNNB1 mutant cancer cells in long-term culture assay in vitro...DMPK and toxicology studies showed robust oral exposure across preclinical species. In summary, CC-91516 has demonstrated preclinical anti-tumor activities and DMPK and safety profiles in support of its clinical development."

Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • CTNNB1 • MAPK1

IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors. (PubMed, Mol Med) - "Our study indicates the essential role of IL4/IL4R signaling for the proliferation of OCPs in early metastasis of CRC predominantly through activating ERK pathway, which remarkedly impacts the number of osteoclasts in later stage and leads to osteolytic lesions. Moreover, Ravoxertinib could be a new therapeutical target for bone metastasis of CRC."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • IL4R

Supervillin Contributes to LPS-induced Inflammatory Response in THP-1 Cell-derived Macrophages. (PubMed, Inflammation) - "Inhibition of TLR4 by Resatorvid (Res) remarkably reversed the LPS-induced SVIL expression. Additionally, inhibition of ERK1/2 signaling pathway (by U0126 or GDC-0994) and NF-κB (by BAY) significantly reduced the LPS-induced SVIL expression...Furthermore, we also observed that SVIL knockdown decreased the proportion of cells in G/M phase and increased the proportion of cells in S & G phase of THP-1 derived macrophages, but did not influence the cell viability. Taken together, we demonstrated that LPS induced the expression of SVIL via activating TLR4/NF-κB and ERK1/2 MAPK pathways, and SVIL participated in the inflammatory response of LPS-induced IL-6, IL-1β and TNF-α upregulation in macrophages."

Journal • Immunology • Inflammation • GSN • IL1B • IL6 • SVIL • TLR4 • TNFA