MK-8353 / Merck (MSD) - LARVOL DELTA

SCAMP3-Driven Regulation of ERK1/2 and Autophagy Phosphoproteomics Signatures in Triple-Negative Breast Cancer. (PubMed, Int J Mol Sci) - "Here, we investigated the role of SCAMP3 in ERK1/2 signaling and therapeutic response using TMT-based LC-MS/MS phosphoproteomics of wild-type (WT) and SCAMP3 knockout (SC3KO) SUM-149 cells under basal conditions, after epidermal growth factor (EGF) stimulation, and during ERK1/2 inhibition with MK-8353...These findings position SCAMP3 as a central coordinator of ERK signaling and autophagy. Our results support SCAMP3 as a potential therapeutic target to enhance ERK1/2 inhibitor clinical efficacy and overcome adaptive resistance mechanisms in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGF • MAP2K2 • SQSTM1

Advances in ERK1/2 inhibition: a medicinal chemistry perspective on structure and regulation. (PubMed, J Enzyme Inhib Med Chem) - "Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics."

Journal • Review • Oncology • MAPK1 • MAPK3

Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013) (clinicaltrials.gov) - P1 | N=111 | Terminated | Sponsor: Merck Sharp & Dohme LLC | Completed ➔ Terminated; business reasons.

Combination therapy • Metastases • Trial termination • Colorectal Cancer • Oncology • Solid Tumor • EGFR • MSI

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

A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors. (PubMed, Invest New Drugs) - P1 | "Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors."

Journal • Metastases • P1 data • Oncology • Solid Tumor

Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors. (PubMed, Invest New Drugs) - P1b | "MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed."

Journal • Metastases • P1 data • Dermatitis • Dermatology • Immunology • Macular Edema • Oncology • Ophthalmology • Retinal Disorders • Solid Tumor • Urticaria

FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation. (PubMed, J Exp Clin Cancer Res) - "This study provided evidence that FBXW7 loss of function promoted ESCC via MAP4 overexpression and ERK phosphorylation, and this novel FBXW7/MAP4/ERK axis may be an efficient target for ESCC treatment."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CHEK1 • FBXW7 • MAP4 • MMP3

S100A1 expression is increased in spinal cord injury and promotes inflammation, oxidative stress and apoptosis of PC12 cells induced by LPS via ERK signaling. (PubMed, Mol Med Rep) - "Furthermore, the overexpression/silencing S100A1 aggravated/mitigated the inflammation, oxidative stress damage and the apoptosis of LPS‑stimulated PC12 cells via the ERK signaling pathway. The present study revealed the mechanism of S100A1 in SCI, which provided a new theoretic reference for future research on SCI."

IO biomarker • Journal • CNS Disorders • Immunology • Inflammation • Orthopedics • BAX • BCL2 • CASP3 • CAT • IL1B • NFE2L2 • TNFA

Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013) (clinicaltrials.gov) - P1 | N=110 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed | N=182 ➔ 110

Combination therapy • Enrollment change • Trial completion • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • MSI

Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014) (clinicaltrials.gov) - P1b; N=30; Completed; Sponsor: Merck Sharp & Dohme Corp.; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Oncology • Solid Tumor

Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014) (clinicaltrials.gov) - P1b; N=30; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Completed ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Oncology • Solid Tumor

Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014) (clinicaltrials.gov) - P1b; N=30; Completed; Sponsor: Merck Sharp & Dohme Corp.; Active, not recruiting ➔ Completed; N=80 ➔ 30; Trial completion date: Sep 2021 ➔ Feb 2021; Trial primary completion date: Sep 2021 ➔ Feb 2021

Clinical • Combination therapy • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013) (clinicaltrials.gov) - P1; N=182; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Recruiting ➔ Active, not recruiting; Trial completion date: Mar 2023 ➔ Sep 2022; Trial primary completion date: Mar 2023 ➔ Sep 2022

Clinical • Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • MSI

Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014) (clinicaltrials.gov) - P1b; N=80; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Recruiting ➔ Active, not recruiting; Trial completion date: Jun 2022 ➔ Sep 2021; Trial primary completion date: Jun 2022 ➔ Sep 2021

Clinical • Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Combined JAK2 and ERK1/2 kinase inhibition as a potent therapeutic approach in myeloproliferative neoplasms (SOHC 2020) - "Our data demonstrate that ERK kinase activation should be targeted to enhance the corrective potential in MPN and that dual inhibition of JAK2 and ERK1/2 increases therapeutic efficacy."

Preclinical

Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013) (clinicaltrials.gov) - P1; N=182; Recruiting; Sponsor: Merck Sharp & Dohme Corp.; N=96 ➔ 182

Clinical • Combination therapy • Enrollment change • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • MSI

[VIRTUAL] Combined JAK2 and ERK1 / 2 kinase inhibition as a new therapeutic approach for myeloproliferative neoplasias (DGHO 2020) - " We assessed ERK inhibitors interfering with ATP binding (LTT462, MK8353) or ERK dimerization (DEL22379) as single agents and in combination with the JAK2 inhibitor ruxolitinib. Our data demonstrate that dual inhibition of JAK2 and ERK1/2 enhances the corrective potential in MPN indicating that ERK kinases should be targeted to increase therapeutic efficacy."

Fibrosis • Hematological Disorders • Immunology • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombocytosis • CD34 • DUSP6 • JAK2

[VIRTUAL] Combined JAK2 and ERK1 / 2 kinase inhibition as a new therapeutic approach for myeloproliferative neoplasias (DGHO 2020) - " We assessed ERK inhibitors interfering with ATP binding (LTT462, MK8353) or ERK dimerization (DEL22379) as single agents and in combination with the JAK2 inhibitor ruxolitinib. Our data demonstrate that dual inhibition of JAK2 and ERK1/2 enhances the corrective potential in MPN indicating that ERK kinases should be targeted to increase therapeutic efficacy."

Fibrosis • Hematological Disorders • Immunology • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombocytosis • CD34 • DUSP6 • JAK2

[VIRTUAL] Combined JAK2 and ERK1 / 2 kinase inhibition as a new therapeutic approach for myeloproliferative neoplasias (DGHO 2020) - " We assessed ERK inhibitors interfering with ATP binding (LTT462, MK8353) or ERK dimerization (DEL22379) as single agents and in combination with the JAK2 inhibitor ruxolitinib. Our data demonstrate that dual inhibition of JAK2 and ERK1/2 enhances the corrective potential in MPN indicating that ERK kinases should be targeted to increase therapeutic efficacy."

Fibrosis • Hematological Disorders • Immunology • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombocytosis • CD34 • DUSP6 • JAK2

[VIRTUAL] Combined JAK2 and ERK1 / 2 kinase inhibition as a new therapeutic approach for myeloproliferative neoplasias (DGHO 2020) - " We assessed ERK inhibitors interfering with ATP binding (LTT462, MK8353) or ERK dimerization (DEL22379) as single agents and in combination with the JAK2 inhibitor ruxolitinib. Our data demonstrate that dual inhibition of JAK2 and ERK1/2 enhances the corrective potential in MPN indicating that ERK kinases should be targeted to increase therapeutic efficacy."

Fibrosis • Hematological Disorders • Immunology • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombocytosis • CD34 • DUSP6 • JAK2

Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013) (clinicaltrials.gov) - P1; N=96; Recruiting; Sponsor: Merck Sharp & Dohme Corp.; Trial completion date: Oct 2021 ➔ Mar 2023; Trial primary completion date: Oct 2021 ➔ Mar 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR

Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013) (clinicaltrials.gov) - P1; N=96; Recruiting; Sponsor: Merck Sharp & Dohme Corp.; Trial primary completion date: Mar 2020 ➔ Dec 2020

Trial primary completion date • Biosimilar • Colorectal Cancer

S100A12 promotes inflammation and apoptosis in ischemia/reperfusion injury via ERK signaling in vitro study using PC12 cells. (PubMed, Pathol Int) - "Similarly, ERK inhibitor MK-8353 reversed the effects of S100A12 overexpression. In conclusion, S100A12 promoted OGD/R-induced inflammation, oxidative stress and apoptosis via activation of ERK signaling in vitro."

Journal • Preclinical

Targeting ERK1/2 protein-serine/threonine kinases in human cancers. (PubMed, Pharmacol Res) - "The best treatments include the combination of B-Raf and MEK inhibitors (dabrafenib and trametinib, encorafenib and binimetinib, vemurafenib and cobimetanib)...Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors...The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway."

Journal • Review

Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. (PubMed, JCI Insight) - P1; "MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters."

Clinical • Journal