temuterkib (LY3214996) / Eli Lilly - LARVOL DELTA

Temporal multiomic profiling reveals intrinsic resistance mechanisms to ERK inhibition in relapsed Acute Myeloid Leukemia (ASH 2025) - P1 | "Temuterkib produced acute on‑target ERK suppression without objective clinical responsesin R/R AML regardless of RAS mutation status. RAS mutations did not confer increased sensitivity to ERKinhibition and may instead attenuate downstream suppression. Rapid induction of JAK-STAT and MTORsignaling may underlie resistance to ERK inhibition in AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • AKT1 • DUSP1 • DUSP6 • EGR1 • FLT3 • KRAS • MYC • NRAS • PTPN11 • RUNX1 • STAT5B • TP53

Oncogenic PLCG1 drives aberrant intra- and intercellular T cell activation. (SITC 2025) - "Notably, co-treatment with the ERK inhibitor LY3214996 effectively reversed SAHA resistance induced by PLCG1 mutations...Supporting these findings, bulk RNA-seq analysis of ATLL patient samples revealed elevated expression of both alpha smooth muscle actin and ICAM1 compared to healthy donors.Conclusions These findings provide mechanistic insights into hyperactive PLCG1 signaling in T-cell malignancies implicating both intracellular LAT-ERK axis and intercellular ICAM1-LFA-1-ERK axis. Our study highlights a potential combinatorial therapeutic strategy employing ERK inhibition to overcome resistance to HDAC inhibitors in cancers."

IO biomarker • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • ICAM1 • PLCG1

Inhibition, But Not Depletion, of Erk Signaling Ameliorates Anthracycline-Induced Cardiotoxicity in Zebrafish. (PubMed, JACC CardioOncol) - "Aberrant Erk activation contributes to AIC, and controlled Erk inhibition may offer therapeutic benefit, potentially via antiaging mechanisms. However, optimization is essential, as excessive inhibition can be cardiotoxic."

Journal • Cardiomyopathy • Cardiovascular • Oncology

RAS pathway inhibitors combined with targeted agents are active in patient-derived spheroids with oncogenic KRAS variants from multiple cancer types. (PubMed, Cancer Res Commun) - "Vertical inhibition of the RAS/MEK/ERK pathway by targeting SHP2 or SOS1 and the downstream kinases MEK (trametinib) or ERK (temuterkib) was highly effective. Inhibition of upstream tyrosine receptor kinases with nintedanib in combination with batoprotafib or BI-3406 was also effective, and in combination with sotorasib, demonstrated synergy in spheroids harboring KRAS G12C. Dual inhibition of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways by batoprotafib or sotorasib with either the mTORC1/2 inhibitor sapanisertib or the AKT inhibitor ipatasertib demonstrated combination activity, primarily in spheroids harboring KRAS G12C. The BCL-2 inhibitor venetoclax in combination with sotorasib, batoprotafib or BI-3406 resulted in additive and synergistic cytotoxicity. Lastly, concurrent inhibition of the KRAS pathway with sotorasib and batoprotafib demonstrated combination activity in spheroids containing KRAS G12C."

Journal • Oncology • KRAS

Fibroblast growth factor 19 regulates polycystic ovary syndrome progression via FGFR4-ERK-NRF2 pathway. (PubMed, Front Cell Dev Biol) - "However, LY3214996 reversed the action of FGF19 overexpression in KGN cells...Conversely, FGF19 overexpression had opposite effects on NRF2 knockdown. FGF19 may be involved in PCOS occurrence and development through the regulation of the FGFR4-ERK-NRF2 pathway."

IO biomarker • Journal • Polycystic Ovary Syndrome • BCL2 • FGF19 • FGFR4 • IL2 • STAT5

Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer. (PubMed, JCO Precis Oncol) - "LY3214996 alone or in combination with HCQ did not result in clinical activity in patients with metastatic PDAC."

Clinical • Journal • P2 data • Anorexia • Hematological Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor

Open-label phase Ib/II study of cetuximab (CET) plus LY3214996 with or without abemaciclib in patients (pts) with anti-EGFR-refractory metastatic colorectal cancer (mCRC). (ASCO 2025) - P1/2 | "CET + LY3214996 ± Abemaciclib had a manageable safety profile with no unexpected adverse events. Although activity was modest, this study is the first to report objective responses to an EGFRi-based regimen in pts harboring acquired RAS mutations in pre-rechallenge ctDNA. Translational efforts are ongoing."

Clinical • Metastases • P1/2 data • Anemia • Colorectal Cancer • Fatigue • Oncology • Solid Tumor • Thrombocytopenia • BRAF • MAP2K1

PADI1 aggravates endoplasmic reticulum stress in trophoblast cells by inhibiting the FAK-ERK signaling pathway. (PubMed, Tissue Cell) - "In conclusion, PADI1 was highly expressed in the placental tissues of PE patients. PADI1 knockdown inhibited the ERS-induced apoptosis in trophoblast cells through FAK/ERK1/2 signaling pathway, suggesting the potential role of PADI1 in PE prevention and treatment."

Journal • Gynecology • ATF6 • HSPA5 • XBP1

Unveiling the Impact of VEGFR2/KDR Modulation on Pulmonary Microvascular Endothelial Cells in COPD/Emphysema (ATS 2025) - "Prior to shear stress, MVECs were treated with VEGFR2 inhibitor SU5416, shKDR, and ERK and Akt inhibitors or relevant controls (DMSO or pLKO)...Similar morphological disturbances and increased apoptosis occurred with the ERK inhibitor temuterkib, emphasizing the importance of the ERK pathway. Conversely, the Akt inhibitor ipatasertib did not significantly affect cell alignment but disturbed elongation... VEGFR2/KDR is decreased in COPD/emphysema. VEGFR2 signaling via the pY1175-VEGFR2/ERK pathway is crucial for maintaining endothelial integrity under shear stress by regulating cell morphology and barrier function via integrin β3. These findings highlight the importance of VEGFR2 in preserving the structural and functional integrity of MVECs and suggest that targeting VEGFR2 signaling may offer therapeutic potential in COPD/emphysema."

Chronic Obstructive Pulmonary Disease • CNS Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CDH5 • KDR

LY3214996 in Patients With AML Who Are Not Candidates for Standard Therapy (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Completed | N=42 ➔ 17

Enrollment change • Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Mechanism by which low-intensity focused ultrasound promotes angiogenesis and neurogenesis after traumatic brain injury in a rat model via the OXA/MAPK signaling pathway. (PubMed, Neural Regen Res) - "Moreover, the MAPK signaling pathway inhibitor LY3214996 suppressed these effects. Taken together, our findings suggest that low-intensity focused ultrasound enhances angiogenesis and neurogenesis and improves neurological function following traumatic brain injury by regulating the expression of Orexin-A/Orexin-A receptor 1, which activates the MAPK signaling pathway."

Journal • Preclinical • CNS Disorders • Oncology • Vascular Neurology • TNFA

F-box only protein 25-mediated α-actinin 1 upregulation drives ovarian cancer progression via ERK1/2 signaling in tumor cells and macrophage M2 polarization. (PubMed, Int Immunopharmacol) - "Upregulation of ACTN1 by FBXO25 promotes the progression of ovarian cancer by activating the ERK1/2 signaling pathway and M2 polarization of macrophages. The FBXO25/ACTN1/ERK1/2 axis and M2 macrophages may represent promising targets for developing ovarian cancer treatments."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CD163

LY3214996 Plus Abemaciclib in Recurrent Glioblastoma Patients (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: Nader Sanai | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2025 ➔ Feb 2028

Enrollment closed • Trial completion date • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CDK4 • CDKN2A • CDKN2B

SHERPA: Combination Therapy of RMC-4630 and LY3214996 in Metastatic KRAS Mutant Cancers (clinicaltrials.gov) - P1 | N=24 | Terminated | Sponsor: The Netherlands Cancer Institute | N=55 ➔ 24 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2024 ➔ Jul 2024; Due to a lack of safety and efficacy.

Enrollment change • Trial primary completion date • Trial termination • Colorectal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Mechanistic Modeling of Spatial Heterogeneity of Drug Penetration and Exposure in the Human Central Nervous System and Brain Tumors. (PubMed, Clin Pharmacol Ther) - "The model was validated by comparisons of model predictions and clinically observed data of six drugs (abemaciclib, ribociclib, pamiparib, olaparib, temuterkib, and ceritinib) in glioblastoma patients. The 9-CNS model is a first-of-its kind, mechanism-based computational modeling platform that enables early reliable prediction of spatial CNS and tumor pharmacokinetics based on plasma concentration-time profiles. It provides a valuable tool to assist rational drug development and treatment for brain cancer."

Heterogeneity • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Analysis of nitrogen metabolism-related gene expression in hepatocellular carcinoma to establish relevant indicators for prediction of prognosis and guidance of immunotherapy. (PubMed, Comput Methods Biomech Biomed Engin) - "This work created a 12-gene signature based on NM, preliminary investigated immune infiltration in two risk categories, and discovered some possible anti-tumor medications. To sum up, our study findings offer fresh perspectives on the roles played by NM-associated genes in HCC development, prognosis, immunological response, and medication screening."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • SPHK1 • YARS1

Effects of ERK1/2 Inhibitors on the Growth of Acute Leukemia Cells. (PubMed, Anticancer Res) - "ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations."

Journal • Acute Myelogenous Leukemia • CNS Tumor • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Solid Tumor • MYC • NRAS

ITGB1 Alleviates High Glucose-Induced Myocardial Cell Injury by Inhibiting Endoplasmic Reticulum Stress and Cell Apoptosis. (PubMed, Int Heart J) - "In conclusion, ITGB1 alleviates high glucose-induced myocardial cell injury by activating the FAK/ERK singling pathway in myocardial cells. This research contributed to the understanding of the pathogenesis of diabetic cardiopathy and the development of novel drugs and therapeutic targets for it."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • ATF6 • CASP12 • HSPA5 • ITGB1 • XBP1

A phase 0/2 trial of abemaciclib plus LY3214996 in recurrent glioblastoma. (SNO 2024) - P1 | "Abemaciclib and LY3214996 achieved pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue in 80% and 30% of the patients, respectively. Suppression of the RB pathway and tumor proliferation, but not ERK pathway was observed. Inadequate CNS penetration and tumor PD modulation by LY3214996 contributed to the unremarkable clinical efficacy profile of this drug combination."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CDKN2A • CDKN2B • RB1

The splicing factor SMNDC1 facilitates alternative RNA splicing, contributing to therapy resistance in pancreatic cancer. (AACRPanCa 2024) - "The standard treatment for PDAC involves chemotherapy, either with Gemcitabine (GEM) combined with paclitaxel or the FOLFIRINOX regimen (5-fluorouracil (5FU), leucovorin, irinotecan, oxaliplatin)...Using these models, we found that SMNDC1 and MAPK3 E4 retention is significantly increased in GEM, 5FU (chemotherapy agents), Adagrasib, Sotorasib (KRAS inhibitors; KRASi G12C), and Selumetinib (MEK inhibitor; MEKi) resistant PDAC cells. Additionally, PDAC lines acutely treated (24h) with trametinib or selumetinib (MEKi) showed a doubling in the expression of SMNDC1 and MAPK3 E4 retention. Protein expression analysis via western blotting revealed that GEM, 5FU, Adagrasib, MRTX1133 (KRASi G12D), and Selumetinib resistant PDAC cells upregulated SMNDC1 expression compared to their sensitive counterparts...To determine if increased E4 retention is a resistance mechanism specific to therapies targeting upstream of ERK1, we treated PDAC cells, proficient and deficient in SMNDC1,..."

Gastrointestinal Cancer • Hepatology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MAPK3

An open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer. (AACRPanCa 2024) - "Hydroxychloroquine (HCQ) is an inhibitor of autophagy and functions by inhibiting acidification of lysosomes...Exploratory analysis using patient-derived organoids did not show evidence of synergistic anti-tumor activity of LY3214996 in combination with chloroquine. LY3214996 alone or in combination with HCQ did not result in clinically meaningful activity in patients with metastatic pancreatic cancer. Further studies are needed to evaluate optimal strategies for autophagy inhibition, as well as combination strategies with other ERK MAPK targets (i.e., KRAS inhibitors) to fully elucidate the role of autophagy as a driver of resistance to ERK MAPK inhibition."

Clinical • Combination therapy • Metastases • P2 data • Acute Kidney Injury • Anorexia • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Nephrology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Renal Disease • Solid Tumor • KRAS

Identifying synergistic combinations with KRAS inhibition in PDAC (AACRPanCa 2024) - "We performed targeted in vivo CRISPRa screening for drivers of resistance to KRASi in an autochthons model of lung adenocarcinoma (LUAD) using a library targeting 452 genes commonly amplified or mutated in cancer. We identified a set of genes that were specifically enriched in at least 50% of tumors treated with MRTX1133, including MAPK1/ERK2. We also generated 16 cell lines with acquired resistance to MRTX1133, derived from KPC PDAC or KPP LUAD tumors."

Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MAPK1

Elucidation of metabolic resistance mechanisms to RAS inhibition (AACRPanCa 2024) - P1, P2 | "We previously determined that concurrent inhibition of autophagy, using the lysosomal inhibitor chloroquine (CQ), and of ERK, using a small molecule ERK inhibitor (ERKi), synergistically suppressed the growth of pancreatic ductal adenocarcinoma (PDAC) cell lines and patient xenograft-derived (PDX) organoids in vitro and PDX tumors in vivo. Our findings provided the rationale for our initiation of Phase I and Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with hydroxychloroquine (HCQ) in PDAC...PIKfyve inhibition with apilimod resulted in a potent reduction of autophagic flux and growth...We hypothesize that further dissection of the dynamic regulation of autophagy and macropinocytosis will improve current anti-nutrient scavenging treatment strategies. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for..."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Concurrent inhibition of the RAS ERK-MAPK pathway and PIKfyve as a therapeutic strategy for pancreatic cancer (AACRPanCa 2024) - P2 | "Furthermore, we demonstrated that concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK MAPK inhibitors synergistically blocked PDAC growth. These findings provided rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT4132505) or ERKi (LY3214996; NCT04386057) with HCQ in PDAC...We demonstrated that PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment...Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings implicate PIKfyve as an effective anti-autophagy target when paired with RAS or ERK-MAPK pathway inhibition in pre-clinical models of PDAC."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • LAMP1

A drug discovery pipeline for MAPK/ERK pathway inhibitors in C. elegans. (PubMed, Cancer Res Commun) - "Using fluorescence-based image analysis of vulva development as a readout for MAPK/ERK activity, we obtained excellent assay Z-scores for the MEK inhibitors trametinib (Z = 0.95), mirdametinib (Z = 0.93), and AZD8330 (Z = 0.87), as well as the ERK inhibitor temuterkib (Z = 0.86). To validate the model in a high throughput setting, we screened a blinded library of 433 anti-cancer compounds and identified four MEK inhibitors among seven positive hits. Our results highlight a high degree of pharmacological conformity between C. elegans and human MAPK/ERK pathways and the presented high-throughput pipeline may discover and characterize novel inhibitors in vivo."

Journal • Oncology