LY3009120 / Eli Lilly, Ono Pharma - LARVOL DELTA

Targeting acute myeloid leukemia resistance with two novel combinations demonstrate superior efficacy in TP53, HLA-B, MUC4 and FLT3 mutations. (PubMed, Biomed Pharmacother) - "Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model...Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • HLA-B • JAK1 • JAK2 • MUC4 • TP53

1,2-Naphthoquinone promotes cell migration through EGFR-ERK signaling pathway in human A549 cells. (PubMed, J Toxicol Sci) - "This activation is significantly suppressed by anti-EGFR antibodies (cetuximab and panitumumab) and inhibitors targeting rapidly accelerated fibrosarcoma (Raf; LY3009120) and mitogen-activated protein kinase kinase (MEK; U0126). Notably, suppression of EGFR-ERK1/2 signaling resulted in a decrease in migratory activity. Our findings provide new insights into lung cancer carcinogenesis and may contribute to the development of novel therapeutic strategies."

Journal • Fibrosarcoma • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor

Mechanism of dimer selectivity and binding cooperativity of BRAF inhibitors. (PubMed, Elife) - "Here, we report extensive molecular dynamics (MD) simulations of the monomeric and dimeric BRAFV600E in the apo form or in complex with one or two dimer-selective (PHI1) or equipotent (LY3009120) inhibitor(s)...Simulations also revealed that the positive cooperativity of PHI1 is due to its ability to preorganize the αC and DFG conformation in the opposite protomer, priming it for binding the second inhibitor. The atomically detailed view of the interplay between BRAF dimerization and inhibitor allostery as well as cooperativity has implications for understanding kinase signaling and contributes to the design of protomer selective RAF inhibitors."

Journal • Oncology

Evaluation of Pan-RAF Inhibitor LY3009120 on Human Uveal Melanoma Cell Line 92-1. (PubMed, Anticancer Res) - "The pan-RAF inhibitor LY3009120 demonstrated a significant anti-tumor effect on human UM cell line 92-1 independent of the molecular BRAF and RAS mutational status."

Journal • Preclinical • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BRAF • KRAS • NRAS • TP53

CORE TARGETS INTERACTOMICS UNVEILED THE MECHANISM OF ACTION IN NOVEL DRUG COMBINATORIAL THERAPY OF AML (EHA 2024) - "The deployment of the PISA technique and our specialized data analysis workflow has successfully pinpointedcritical drug targets and their mechanisms within AML. This exploration brings to light the significant potentialof the ruxolitinib-ulixertinib and LY3009120-sapanisertib combinations to transcend traditional treatmentbarriers and engage essential metabolic pathways, including the central carbon metabolism. These findingsadvocate for a new direction in AML treatment strategy development, promising more effective and preciselytargeted therapies that could lead to better patient outcomes."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

EVALUATING THE EFFICACY OF PATIENT-ORIENTED COMBINATION THERAPIES FOR AML VIA EX VIVO AND IN VIVO MODELS (EHA 2024) - "This study utilized a data mining approach to address limitations of traditional AML therapy, including drugresistance, limited efficacy, and lack of targeted treatment. We identified two synergistic drug combinations,Ruxolitinib & ulixertinib and sapanisertib & LY3009120, exhibiting high efficacy against AML blasts withminimal impact on healthy cells. In vivo assays using xenografted zebrafish further supported the efficiency ofthese combinations compared to single agents and controls."

Combination therapy • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD14 • GAPDH

Biochemical and cell-based assay platforms for development of RAF inhibitors against human cancers (AACR 2024) - "Here, we demonstrate that the 3rd generation of pan-RAF inhibitors LY3009120, LXH254, and Belvarafenib inhibit ARAF, BRAF, CRAF, BRAF(V600E), and CRAF(R391W) kinase activity in biochemical HotSpotTM assay. Furthermore, our results show these inhibitors can block the downstream ERK phosphorylation in cellular HTRF assay and induce caspase-3/7 activation in Western blot assay in the triple negative breast cancer MDA-MB-231 cells. Taken together, our results indicate the biochemical HotSpotTM kinase activity assay, and NanoBRETTM target engagement and NanoBITTM cellular assays can serve as great platforms to facilitate RAF drug discovery against human cancers."

Breast Cancer • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • ARAF • BRAF • CASP3 • CASP7 • KRAS

DOCK1 regulates the malignant biological behavior of endometrial cancer through c-Raf/ERK pathway. (PubMed, BMC Cancer) - "DOCK1 could enhance the malignant biological behavior of endometrial cancer cells, which might be through c-RAF/ERK1/2 signaling pathways in vitro and in vivo."

IO biomarker • Journal • Endometrial Cancer • Oncology • Solid Tumor • Transplantation • BCL2 • CDH1 • DOCK1 • EZR • MMP9 • RAF1

Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120's Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines. (PubMed, Genes (Basel)) - "The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the NRAS p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology."

Journal • Preclinical • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF • KRAS • NRAS

The combination of osimertinib with Raf inhibitor overcomes osimertinib resistance induced by KRAS amplification in EGFR-mutated lung cancer cells. (PubMed, Exp Cell Res) - "We established cell lines with acquired resistance to osimertinib from gefitinib- or erlotinib-resistant NSCLC cells using a dose-escalation method, and found that they had upregulated levels of phosphorylated ERK1/2. Combined treatment with osimertinib and LY3009120 also demonstrated remarkable synergistic anti-tumor activity in mouse xenografts of these cells. This could be a potential new treatment option for KRAS amplification-induced osimertinib failure."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS

Differential regulation of histamine H receptor-mediated ERK phosphorylation by G proteins and arrestins. (PubMed, Biochem Pharmacol) - "Inhibitors of G proteins (YM-254890) and protein kinase C (PKC) (GF109203X), and an intracellular Ca chelator (BAPTA-AM) suppressed histamine-induced ERK phosphorylation in cells expressing S487TR, but not those expressing S487A. Conversely, inhibitors of G protein-coupled receptor kinases (GRK2/3) (cmpd101), β-arrestin2 (β-arrestin2 siRNA), clathrin (hypertonic sucrose), Raf (LY3009120), and MEK (U0126) suppressed histamine-induced ERK phosphorylation in cells expressing S487A, but not those expressing S487TR. These results suggest that H receptor-mediated ERK phosphorylation might be differentially regulated by the G protein/Ca/PKC and GRK/arrestin/clathrin/Raf/MEK pathways to potentially determine the early and late phases of histamine-induced allergic and inflammatory responses, respectively."

Journal • Inflammation • ARRB1

Estimated sensitivity profiles of lung cancer specific uncommon BRAF mutants towards experimental and clinically approved kinase inhibitors. (PubMed, Toxicol Appl Pharmacol) - "All the uncommon mutants displayed higher sensitivity than both the wild type and BRAF-V600E towards PLX 8394 and LSN3074753...Notably, molecular dynamic (MD) simulation revealed that increased number of interactions caused enhanced sensitivity of G469R and N581S towards sorafenib. RAF kinase inhibitors were further classified into two groups as per their selectivity (Group I: BRAF-V600E-selective and Group II: CRAF-selective) based on which potential mutation-wise combinations of RAF kinase inhibitors were proposed to overcome resistance. Based on computational inhibitor sensitivity profiles, appropriate treatment strategies may be devised to prevent or overcome secondary drug resistance in lung cancer patients with uncommon mutations."

Journal • Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • KRAS

Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors. (PubMed, Proc Natl Acad Sci U S A) - "In this study, we showed that LY3009120, a pan-RAF inhibitor, can unexpectedly cause paradoxical ERK activation in KRAS-dependent lung cancer cell lines, when KRAS is inhibited by ARS1620, a KRAS inhibitor. We further showed that the MRAS/SHOC2 complex is required for this process. This study highlights the complexity of the allosteric RAF regulation by RAF inhibitors, and the importance of other RAS-related proteins in this process."

Journal • Lung Cancer • Oncology • Solid Tumor • KRAS

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity. (PubMed, Int J Pharm X) - "To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120...For formulations 57-1, 59-4, and 59-5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time."

Journal

Exploiting LY3009120 and Asciminib Combination to Target TKI-Resistant CML (ASH 2021) - "To identify functional ponatinib analogs, we performed Quantum Similarity Modeling (QSM) on the reported crystal structure of T315I mutant ABL1 kinase in complex with nilotinib and asciminib (5MO4) (Wylie et al. In summary, our findings validate QSM as a novel in silico approach to identify TKI combinations. Combining LY3009120 with asciminib may be an effective, low-risk strategy to target BCR-ABL1 compound mutants in patients with clinical TKI resistance."

Acute Lymphocytic Leukemia • Cardiovascular • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ABL1 • BCR

High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma. (PubMed, Transl Oncol) - "MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor • BRAF

TM7SF2 regulates cell proliferation and apoptosis by activation of C-Raf/ERK pathway in cervical cancer. (PubMed, Cell Death Discov) - "Further, we found that TM7SF2 participated in promoting tumorigenesis and progression via activation of C-Raf/ERK pathway in cervical cancer, which can be partly reversed by Raf inhibitor LY3009120...Our findings indicated that TM7SF2 plays a vital role in tumor promotion by involving in C-Raf/ERK activation. Therefore, TM7SF2 could serve as a therapeutic target in future cervical cancer treatment."

Journal • Cervical Cancer • Oncology • Solid Tumor • RAF1

Pan-RAF inhibitor LY3009120 is highly synergistic with low-dose cytarabine, but not azacitidine, in acute myeloid leukemia with RAS mutations. (PubMed, Oncol Lett) - "In addition, we confirmed that combination treatment with low-dose cytarabine and LY3009120 led to an increase in apoptosis in primary AML cells. Our findings indicate that combination therapy with pan-RAF inhibitor LY3009120 and low-dose cytarabine may be a promising treatment strategy for RAS-mutated AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KRAS • NRAS

Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition. (PubMed, Cancers (Basel)) - "Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea...Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCL2L1 • BCR • FLT3

Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers. (PubMed, Sci Rep) - "A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies."

Clinical • Journal • Biliary Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Small Intestinal Carcinoma • Solid Tumor • BRAF • EGFR • KRAS

BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers. (PubMed, Pediatr Blood Cancer) - "In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition."

Clinical • Journal • Hematological Malignancies • Oncology • Pediatrics

Pan-RAF Inhibition Shows Anti-Leukemic Activity in RAS-Mutant Acute Myeloid Leukemia Cells and Potentiates the Effect of Sorafenib in Cells with FLT3 Mutation. (PubMed, Cancers (Basel)) - "Furthermore, the combination of LY3009120 and sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using LY3009120 results in anti-leukemic activity, and combination with Ara-C or sorafenib potentiates its effect."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology